Epothilone derivatives, method for producing same and their pharmaceutical use

ABSTRACT

This invention relates to the new epothilone derivatives of general formula I, 
                         
in which
 
     substituents Y, Z, R 2a , R 2b , R 3 , R 4a , R 4b , D-E, R 5 , R 6 , R 7 , R 8  and X have the meanings that are indicated in more detail in the description. 
     The new compounds interact with tubulin by stabilizing microtubuli that are formed. They are able to influence the cell-splitting in a phase-specific manner and are suitable for treating malignant tumors, for example, ovarian, stomach, colon, adeno-, breast, lung, head and neck carcinomas, malignant melanomas, acute lymphocytic and myelocytic leukemia. In addition, they are suitable for anti-angiogenesis therapy as well as for treatment of chronic inflammatory diseases (psoriasis, arthritis). To avoid uncontrolled proliferation of cells and for better compatibility of medical implants, they can be applied or introduced into polymer materials. 
     The compounds according to the invention can be used alone or to achieve additive or synergistic actions in combination with other principles and classes of substances that can be used in tumor therapy.

Höfle et al. describe the cytotoxic action of the natural productsepothilone A (R=hydrogen) and epothilone B (R=methyl)

Epothilone A (R=H), Epothilone B (R=CH₃) in, e.g., Angew. Chem. [AppliedChem.], 1996, 108, 1671-1673. Because of their in-vitro selectivity forbreast cell lines and intestinal cell lines and their significantlyhigher activity against P-glycoprotein-forming multiresistant tumorlines in comparison to taxol as well as their physical properties thatare superior to those of taxol, e.g., a water solubility that is higherby a factor of 30, this novel structural class is especiallyadvantageous for the development of a pharmaceutical agent for treatingmalignant tumors.

The natural products are not sufficiently stable either chemically ormetabolically for the development of pharmaceutical agents. To eliminatethese drawbacks, modifications to the natural product are necessary.Such modifications are possible only with a total-synthesis approach andrequire synthesis strategies that make possible a broad modification ofthe natural product. The purpose of the structural changes is also toincrease the therapeutic range. This can be done by improving theselectivity of the action and/or reducing undesirable toxic side-effectsand/or increasing active strength.

The total synthesis of epothilone A is described by Schinzer et al. inChem. Eur. J. 1996, 2, No. 11, 1477-1482 and in Angew. Chem. 1997, 109,No. 5, pp. 543-544).

Epothilone derivatives were already described by Höfle et al. in WO97/19086. These derivatives were produced starting from naturalepothilone A or B.

Another synthesis of epothilone and epothilone derivatives was describedby Nicolaou et al. in Angew. Chem. 1997, 109, No. 1/2, pp. 170-172. Thesynthesis of epothilone A and B and several epothilone analogues wasdescribed in Nature, Vol. 387, 1997, pp. 268-272; and the synthesis ofepothilone A and its derivatives was described in J. Am. Chem. Soc.,Vol. 119, No. 34, 1997, pp. 7960-7973 as well as the synthesis ofepothilone A and B and several epothilone analogues in J. Am. Chem.Soc., Vol. 119, No. 34, 1997, pp. 7974-7991 also by Nicolaou et al.

Nicolaou et al. also describe in Angew. Chem. 1997, 109, No. 19, pp.2181-2187 the production of epothilone A analogues using combinativesolid-phase synthesis. Several epothilone B analogues are also describedthere.

The object of this invention consists in making available new epothilonederivatives, which are both chemically and metabolically stable enoughfor the development of pharmaceutical agents and which are superior tonatural derivatives in terms of their therapeutic range, theirselectivity of action and/or undesirable toxic side-effects and/or theiractive strength.

This invention describes the new epothilone derivatives of generalformula I,

in which

-   -   R^(1a), R^(1b) are the same or different and mean hydrogen,        C₁-C₁₀ alkyl, aryl, C₇-C₂₀ aralkyl, or together a —(CH₂)_(m)        group with m=2, 3, 4 or 5,    -   R^(2a), R^(2b) are the same or different and mean hydrogen,        C₁-C₁₀ alkyl, aryl, C₇-C₂₀ aralkyl or together a —(CH₂)_(n)        group with n=2, 3, 4 or 5, whereby, if -D-E-stands for —CH₂—CH₂—        or Y stands for an oxygen atom, R^(2a)/R^(2b) cannot be        hydrogen/methyl,    -   R³ means hydrogen, C₁-C₁₀ alkyl, aryl, C₇-C₂₀ aralkyl,    -   R^(4a), R^(4b) are the same or different and mean hydrogen,        C₁-C₁₀ alkyl, aryl, C₇-C₂₀ aralkyl or together a —(CH₂)_(p)        group with p=2, 3, 4 or 5,

-   -   D-E means a group    -   R⁵ means hydrogen, C₁-C₁₀ alkyl, aryl, C₇-C₂₀ aralkyl,    -   R⁶, R⁷ each mean a hydrogen atom, together an additional bond or        an oxygen atom,    -   R⁸ means hydrogen, C₁-C₂₀ alkyl, aryl, C₇-C₂₀ aralkyl, which can        all be substituted,    -   X means an oxygen atom, two alkoxy groups OR²³, a C₂-C₁₀        alkylene-α,ω-dioxy group, which can be straight-chain or        branched, H/OR⁹ or a grouping CR¹⁰R¹¹,        -   whereby        -   R²³ stands for a C₁-C₂₀ alkyl radical,        -   R⁹ stands for hydrogen or a protective group PG^(x),        -   R¹⁰, R¹¹ are the same or different and stand for hydrogen, a            C₁-C₂₀ alkyl, aryl, C₇-C₂₀ aralkyl radical or R¹⁰ and R¹¹            together with the methylene carbon atom together stand for a            5- to 7-membered carbocyclic ring,    -   Y means an oxygen atom or two hydrogen atoms,    -   Z means an oxygen atom or H/OR¹²,        -   whereby        -   R¹² means hydrogen or a protective group PG^(z).

The production of the new epothilone derivatives is based on the linkageof three partial fragments A, B and C. The interfaces are as indicatedin general formula I′.

A means a C1-C6 fragment (epothilone numbering system) of generalformula

in which

-   -   R^(1a′), R^(1b′), R^(2a′) and R^(2b′) have the meanings already        mentioned for R^(1a), R^(1b), R^(2a) and R^(2b), and    -   R¹³ means CH₂OR^(13a), CH₂-Hal, CHO, CO₂R^(13b), COHal,    -   R¹⁴ means hydrogen, OR^(14a), Hal, OSO₂R^(14b),    -   R^(13a), R^(14a) mean hydrogen, SO₂-alkyl, SO₂-aryl, SO₂-aralkyl        or together a —(CH₂)_(o) group or together a CR^(15a)R^(15b)        group,    -   R^(13b), R^(14b) mean hydrogen, C₁-C₂₀ alkyl, aryl, C₇-C₂₀        aralkyl,    -   R^(15a), R^(15b) are the same or different and mean hydrogen,        C₁-C₁₀ alkyl, aryl, C₇-C₂₀ aralkyl or together a —(CH₂)_(q)        group,    -   Hal means halogen,    -   o means 2 to 4,    -   q means 3 to 6,    -   including all stereoisomers as well as their mixtures, and

free hydroxyl groups in R¹³ and R¹⁴ can be etherified or esterified,free carbonyl groups can be ketalized in A and R¹³, converted into anenol ether or reduced, and free acid groups in A can be converted intotheir salts with bases.

B stands for a C7-C12 fragment (epothilone numbering system) of generalformula

in which

-   -   R^(3′), R^(4a′), R^(4b′) and R^(5′) have the meanings already        mentioned for R³, R^(4a), R^(4b) and R⁵,    -   V means an oxygen atom, two alkoxy groups OR¹⁷, a C₂-C₁₀        alkylene-α,ω-dioxy group, which can be straight-chain or        branched or H/OR¹⁶,    -   W means an oxygen atom, two alkoxy groups OR¹⁹, a C₂-C₁₀        alkylene-α,ω-dioxy group, which can be straight-chain or        branched or H/OR¹⁸,    -   R¹⁶, R¹⁸, independently of one another, mean hydrogen or a        protective group PG¹    -   R¹⁷, R¹⁹, independently of one another, mean C₁-C₂₀ alkyl.    -   C stands for a C13-C16 fragment (epothilone numbering system) of        general formula

in which

-   -   R^(8′) has the meaning already mentioned in general formula I        for R⁸, and    -   R^(7′) means a hydrogen atom,    -   R²⁰ means a hydrogen atom or a protective group PG²,    -   R²¹ means a hydroxy group, halogen, a protected hydroxy group        OPG³, a phosphonium halide radical PPh₃ ⁺Hal⁻ (Ph=phenyl; Hal=F,        Cl, Br, I), a phosphonate radical P(O) (OQ)₂ (Q=C₁-C₁₀ alkyl or        phenyl) or a phosphine oxide radical P(O)Ph₂ (Ph=phenyl),    -   U means an oxygen atom, two alkoxy groups OR²³, a C₂-C₁₀        alkylene-α,ω-dioxy group, which can be straight-chain or        branched, H/OR⁹ or a grouping CR¹⁰R¹¹,        -   whereby        -   R²³ stands for a C₁-C₁₀ alkyl radical,        -   R⁹ stands for hydrogen or a protective group PG³,        -   R¹⁰, R¹¹ are the same or different and stand for hydrogen, a            C₁-C₂₀ alkyl, aryl, C₇-C₂₀ aralkyl radical or R¹⁰ and R¹¹            together with the methylene carbon atom together stand for a            5- to 7-membered carbocyclic ring.

As alkyl groups R^(1a), R^(1b), R^(2a), R^(2b), R³, R⁴, R⁵, R⁸, R⁹, R¹⁰,R¹¹, R¹², R^(13b), R^(14b), R^(15a), R^(15b), R¹⁷ and R²³,straight-chain or branched-chain alkyl groups with 1-20 carbon atoms canbe considered, such as, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl,hexyl, and decyl.

Alkyl groups R^(1a), R^(1b), R^(2a), R^(2b), R³, R⁴, R⁵, R⁸, R⁹, R¹⁰,R¹¹, R¹², R^(13b), R^(14b), R^(15a), R^(15b), R¹⁷ and R²³ can beperfluorinated or substituted by 1-5 halogen atoms, hydroxy groups,C₁-C₄ alkoxy groups, C₆-C₁₂ aryl groups (which can be substituted by 1-3halogen atoms).

As aryl radicals R^(1a), R^(1b), R^(2a), R^(2b), R³, R⁴, R⁵, R⁸, R⁹,R¹⁰, R¹¹, R¹², R^(13b), R^(14b), R^(15a) and R^(15b), substituted andunsubstituted carbocyclic or heterocyclic radicals with one or moreheteroatoms, such as, e.g., phenyl, naphthyl, furyl, thienyl, pyridyl,pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl,thiazolyl, which can be substituted in one or more places by halogen,OH, O-alkyl, CO₂H, CO₂-alkyl, —NH₂, —NO₂, —N₃, —CN, C₁-C₂₀ alkyl, C₁-C₂₀acyl, C₁-C₂₀ acyloxy groups, are suitable. Heteroatoms in the heteroarylradicals can be oxidized; thus, for example, the thiazole ring can bepresent in the form of N-oxide.

The aralkyl groups in R^(1a), R^(1b), R^(2a), R^(2b), R³, R⁴, R⁵, R⁸,R⁹, R¹⁰, R¹¹, R¹², R^(13b), R^(14b), R^(15a) and R^(15b) can contain inthe ring up to 14 C atoms, preferably 6 to 10, and in the alkyl chain 1to 8, preferably 1 to 4 atoms. As aralkyl radicals, for example, benzyl,phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl,and pyridinylpropyl are suitable. The rings can be substituted in one ormore places by halogen, OH, O-alkyl, CO₂H, CO₂-alkyl, —NO₂, —N₃, —CN,C₁-C₂₀ alkyl, C₁-C₂₀ acyl, C₁-C₂₀ acyloxy groups.

The alkoxy groups that are contained in X in general formula I are ineach case to contain 1 to 20 carbon atoms, whereby methoxy, ethoxy,propoxy, isopropoxy and t-butyloxy groups are preferred.

As representatives of protective groups PG, alkyl- and/oraryl-substituted silyl, C₁-C₂₀ alkyl, C₄-C₇ cycloalkyl, which inaddition in the ring can contain an oxygen atom, aryl, C₇-C₂₀ aralkyl,C₁-C₂₀ acyl and aroyl can be mentioned.

As alkyl, silyl and acyl radicals for protective groups PG, the radicalsthat are known to one skilled in the art are suitable. Preferred arealkyl or silyl radicals that can be easily cleaved from thecorresponding alkyl and silyl ethers, such as, for example,methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl,tetrahydrofuranyl, trimethylsilyl, triethylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl,triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl radicalsas well as alkylsulfonyl and arylsulfonyl radicals. As acyl radicals,e.g., formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl orbenzoyl, which can be substituted with amino and/or hydroxy groups, aresuitable.

Acyl groups PG^(x) or PG^(z) in R⁹ and R¹² can contain 1 to 20 carbonatoms, whereby formyl, acetyl, propionyl, isopropionyl and pivalylgroups are preferred.

Index m in the alkylene group that is formed from R^(1a) and R^(1b)preferably stands for 2, 3 or 4.

The C₁-C₁₀ alkylene-α,ω-dioxy group that is possible for X is preferablyan ethyleneketal or neopentylketal group.

The substituents can be selected in the compounds of general formula Iin such a way that

Y, Z, R^(1a), R^(1b), R^(2a) and R^(2b) all can have the meanings thatare indicated in general formula I, and the remainder of the molecule isidentical to naturally occurring epothilone A or B, or

R³, R^(4a), R^(4b), D-E, R⁵, R⁶ and R⁷ all can have the meanings thatare indicated in general formula I, and the remainder of the molecule isidentical to naturally occurring epothilone A or B, or

R⁶, R⁷, R⁸ and X all can have the meanings that are indicated in generalformula I, and the remainder of the molecule is identical to naturallyoccurring epothilone A or B, or

Y, Z, R^(1a), R^(1b), R^(1a), R^(2b), R³, R^(4a), R^(4b), D-E, R⁵, R⁶and R⁷ all can have the meanings that are indicated in general formulaI, and the remainder of the molecule is identical to naturally occurringepothilone A or B, or

Y, Z, R^(1a), R^(1b), R^(2a), R^(2b), R⁶, R⁷, R⁸ and X all can have themeanings that are indicated in general formula I, and the remainder ofthe molecule is identical to naturally occurring epothilone A or B, or

R³, R^(4a), R^(4b), D-E, R⁵, R⁶, R⁷, R⁸ and X all can have the meaningsthat are indicated in general formula I, and the remainder of themolecule is identical to naturally occurring epothilone A or B.

The compounds that are mentioned below are preferred according to theinvention:

-   (4S,7R,8S,9S,13(Z),16S(E))-4,8-Dihydroxy-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione,    and-   (4S,7R,8S,9S,13E,16S(E))-4,8-dihydroxy-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione-   (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione    and-   (1R,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (1S,3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazoyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione    and-   (1R,3S(E),7S,10R,11S,12S,16R)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7S,8R,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione    and-   (4S,7S,8R,9S,13E,16S(E))-4,8-dihydroxy-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione-   (1S,3S(E),7S,10S,11R,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,    and-   (1R,3S(E),7S,10S,11R,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (1S,3S(E),7S,10S,11R,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,    and-   (1R,3S(E),7S,10S,11R,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13(Z),16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-((3-pyridyl)ethenyl)-1-oxa-cyclohexadec-13-ene-2,6-dione,    and-   (4S,7R,8S,9S,13E,16S(E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((3-pyridyl)ethenyl)-1-oxa-cyclohexadec-13-ene-2,6-dione-   (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-((3-pyridyl)ethenyl)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,    and-   (1S,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-((3-pyridyl)ethenyl)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13(Z),16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-((4-pyridyl)ethenyl)-1-oxa-cyclohexadec-13-ene-2,6-dione,    and-   (4S,7R,8S,9S,13E,16S(E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((4-pyridyl)ethenyl)-1-oxa-cyclohexadec-13-ene-2,6-dione-   (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-((4-pyridyl)ethenyl)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,    and-   (1S,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-((4-pyridyl)ethenyl)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13(E or    Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-7-phenyl-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione-   (1(S or    R),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-phenyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (1(R or    S),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-phenyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13(E or    Z),16S(E))-7-Benzyl-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione-   (1(S or    R),3S(E),7S,10R,11S,12S,16R)-10-Benzyl-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (1(R or    S),3S(E),7S,10R,11S,12S,16S)-10-Benzyl-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13(E or    Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,7,13-tetramethyl-9-trifluoromethyl-cyclohexadec-13-ene-2,6-dione-   (1(S or    R),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,16-tetramethyl-12-trifluoromethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (1(R or    S),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,16-tetramethyl-12-trifluoromethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,11E/Z,13(E or    Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-11,13-diene-2,6-dione-   (1(S or    R),3S(E),7S,10R,11S,12S,14E/Z,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadec-14-ene-5,9-dione-   (1(R or    S),3S(E),7S,10R,11S,12S,14E/Z,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadec-14-ene-5,9-dione-   (4S,7R,8S,9S,13(E or    Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-11-ine-2,6-dione-   (1(S or    R),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadec-14-ine-5,9-dione-   (1(R or    S),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadec-14-ine-5,9-dione-   (4S,7R,8S,9S,13(E or    Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,7,9-tetramethyl-13-trifluoromethyl-cyclohexadec-13-ene-2,6-dione-   (1(S or    R),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12-tetramethyl-16-trifluoromethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione-   (1(R or    S),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12-tetramethyl-16-trifluoromethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione-   (4S,7R,8S,9S,13(E or    Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-13-pentafluoroethyl-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione-   (1(S or    R),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-16-pentafluoroethyl-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione-   (1(R or    S),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-16-pentafluoroethyl-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione-   (4S,7R,8S,9S,13(E or    Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5-(13-triethylene)-7,9,13-trimethyl-cycohexadec-13-ene-2,6-dione-   (1(S or    R),3S(E),7S,10R,11S,12S,16R)-7,11-(Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8-(1,3-trimethylene)-10,12,16-trimethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione-   (1(R or    S),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8-(1,3-trimethylene)-10,12,16-trimethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione-   (4S,7R,8S,9S,11E/Z,13(E or    Z),16S(E))-4,8-Dihydroxy-13-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,7,9-tetramethyl-cyclohexadec-11,13-diene-2,6-dione-   (1(S or    R),3S(E),7S,10R,11S,12S,14E/Z,16R)-7,11-Dihydroxy-16-ethyl-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadec-14-ene-5,9-dione-   (1(R or    S),3S(E),7S,10R,11S,12S,14E/Z,16S)-7,11-Dihydroxy-16-ethyl-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadec-14-ene-5,9-dione-   (4S,7R,8S,9S,11E/Z,13(E or    Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-13-propyl-5,5,7,9-tetramethyl-cyclohexadec-11,13-diene-2,6-dione-   (1(S or    R),3S(E),7S,10R,11S,12S,14E/Z,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-16-propyl-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadec-14-ene-5,9-dione-   (1(R or    S),3S(E),7S,10R,11S,12S,14E/Z,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-16-propyl-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadec-14-ene-5,9-dione-   (4S,7R,8S,9S,13(E or    Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione-   (1(S or    R),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (1(R or    S),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13(E or    Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(4-pyridyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione-   (1(S or    R),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(4-pyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (1(R or    S),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(4-pyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione-   (4S,7R,8S,9S,13(E or    Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-5,5,7,9,13-pentamethyl-cyclohexadec-13-en-6-one-   (1(S or    R),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadec-9-one-   (1(R or    S),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadec-9-one    Representation of Partial Fragments A:

It is known that the compound of the following formula

can be used to synthesize the C1-C6 fragment (epothilone numberingsystem) of epothilone A (Schinzer et al., Chem. Eur. J. 1996, 2, No. 11,pp. 1477-1482; Schinzer et al., Angew. Chem., 1997, 109, No. 5, pp.543-544).

This way of synthesizing has the drawback that at 10.5% its total yieldis very low, that the necessary introduction of the chirality at C-atom3 requires the synthesis of an expensive, chemically unstable chiraladjuvant that is to be used in equimolar quantities and cannot berecovered, and that at approximately 80% the optical induction that isachieved is incomplete.

For a synthesis that can be used on an industrial scale, however, highyields and high optical purity are required.

In Angew. Chem. 1997, 109, Nos. 1/2, pp. 170-172, a description is givenby Nicolaou et al. of the synthesis of a (C1-C6) component with acarboxyl group at C-1 that can be used for the synthesis of epothiloneor epothilone derivatives

(TBS=tert-butyldimethylsilyl). The stereochemistry at C3 is controlledby the reaction with the Brown reagent allylisopinocamphenylborane(+)-Ipc₂B (allyl) that must be inserted into the reaction in anequimolar fashion and that cannot be recovered.

Likewise, the use of this component to synthesize epothilone A and B andsome epothilone analogues is described by Nicolaou et al. in Nature,Vol. 387, 1997, pp. 268-272, to synthesize epothilone A and itsderivatives in J. Am. Chem. Soc., Vol. 119, No. 34, 1997, pp. 7960-7973,and to synthesize epothilone A and B and some epothilone analogues in J.Am. Chem. Soc., Vol. 119, No. 34, 1997, pp. 7974-7991.

In Angew. Chem. 1997, 109, No. 19, pp. 2181-2187, Nicolaou et al. alsodescribe the production of epothilone A analogues by means ofcombinatorial solid-phase synthesis. This same citation also mentionsepothilone B analogues. The following compounds are used as C1-C6components:

For a synthesis that can be used on an industrial scale, it isadvantageous for the synthesis to be carried out without expensivechiral auxiliaries.

The object was therefore to find an appropriate synthesis that provideshigh yields, produces the desired product at high optical purity, anddoes not require expensive chiral auxiliaries.

In addition, the new synthesis should make it possible to varysubstituents widely in this component and thus, ultimately, in theresulting epothilone derivatives.

The partial fragments (synthesis components) of general formula A can beeasily produced as starting products from

a) a pantolactone of general formula IIa

in which

-   -   R^(1a′), R^(1b′) in each case stand for a methyl group, or    -   b) a malonic acid dialkyl ester of general formula XXVIII

in which

-   -   R^(1a′), R^(1b′) have the meaning that is indicated in general        formula A, and alkyls, independently of one another, mean a        C₁-C₂₀ alkyl, C₃-C₁₀ cycloalkyl or C₄-C₂₀ alkylcycloalkyl        radical.

Partial fragments A, in which R^(1a′)=R^(1b′)=methyl, can be efficientlyproduced from inexpensive pantolactone with an optical purity of >98%.

The synthesis is described in diagram 1 below in the example ofD-(−)-pantolactone. From L-(+)-pantolactone are obtained thecorresponding enantiomeric compounds ent-A-1I to ent-A-XIV in A-II toA-XIV, and from racemic DL-pantolactone are obtained the correspondingracemic compounds rac-A-II to rac-A-XIV:

Step a (A-II

A-III):

The free hydroxy group of pantolactone (A-II) is protected according tothe methods that are known to one skilled in the art. As protectivegroup PG⁴, the protective groups that are known to one skilled in theart, such as, e.g., methoxymethyl, methoxyethyl, ethoxyethyl,tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl,triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, formyl,acetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl radicals,are suitable.

A survey is found in, e.g., “Protective Groups in Organic Synthesis”Theodora W. Green, John Wiley and Sons).

Preferred are those protective groups that can be cleaved under acidicreaction conditions, such as, e.g., methoxymethyl, tetrahydropyranyl,tetrahydrofuranyl, and trimethylsilyl radicals.

Especially preferred is the tetrahydropyranyl radical.

Step b (A-III

A-IV):

Protected lactone A-III is reduced to lactol A-IV. As a reducing agent,aluminum hydrides that are modified in their reactivity, such as, e.g.,diisobutylaluminum hydride, are suitable. The reaction is carried out inan inert solvent such as, e.g., toluene, preferably at low temperatures.

Step c (A-IV

A-V):

Lactol A-IV is opened up to form hydroxyolefin A-V while expanding byone C atom. For this purpose, the methods that are known to one skilledin the art, such as, e.g., olefination according to Tebbe, the Wittig orWittig/Horner reaction, the addition of an organometallic compound withdehydration, are suitable. Preferred is the Wittig reaction with use ofmethyltriarylphosphonium halides such as, e.g.,methyltriphenylphosphonium bromide with strong bases, such as, e.g.,n-butyllithium, potassium-tert-butanolate, sodium ethanolate, sodiumhexamethyldisilazane; as a base, n-butyllithium is preferred.

Step d (A-V

A-VI):

The free hydroxy group in A-V is protected according to the methods thatare known to one skilled in the art. As protective group PG⁵, theprotective groups that are known to one skilled in the art, as werealready mentioned above for PG⁴ in step a (A-II ### A-III), aresuitable.

Preferred are those protective groups that can be cleaved under theaction of fluoride, such as, e.g., the trimethylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl,triisopropylsilyl radical.

Especially preferred is the tert-butyldimethylsilyl, thetriisopropylsilyl and the tert-butyldiphenylsilyl radical.

Step e (A-VI

A-VII):

Water is added to the double bond in A-VI in an anti-Markovnikovorientation. For this purpose, the processes that are known to oneskilled in the art, such as, e.g., reaction with boranes, theirsubsequent oxidation to the corresponding boric acid esters and theirsaponification are suitable. As boranes, e.g., theborane-tetrahydrofuran complex, the borane-dimethyl sulfide complex,9-borabicyclo[3.3.1]nonane in an inert solvent such as, for example,tetrahydrofuran or diethyl ether, are preferred. As oxidizing agents,preferably hydrogen peroxide is used; for saponification of the boronesters, preferably alkali hydroxides, such as, e.g., sodium hydroxide,are used.

Step f (A-VI

A-VII):

Protective group PG⁴ that is introduced under step a) is now cleavedaccording to the processes that are known to one skilled in the art. Ifthis is a protective group that can be cleaved acidically, then cleavagecan be accomplished with dilute mineral acids in aqueous-alcoholicsolutions and with the aid of catalytic quantities of acids, such as,e.g., para-toluenesulfonic acid, para-toluenesulfonic acid-pyridiniumsalt, camphorsulfonic acid in alcoholic solutions, preferably in ethanolor isopropanol.

Step g (A-VII

A-IX):

Common protection of the two alcohol functions of the mono-protected1,3-diol in A-VII is possible under acid catalysis by directketalization with a carbonyl compound of general formulaR^(15a)—CO—R^(15b) or by reketalization with a ketal of general formulasR^(15a)—C(OC₂H₅)₂—R^(15b), R^(15a)—C(OC₂H₄)₂—R^(15b),R^(15a)—C(OCH₂C(C₃)₂CH₂O)—R^(15b), in which in each case R^(15a) andR^(15b) have the above-indicated meanings. As acids, the acids alreadymentioned under step f) are suitable; the use of para-toluenesulfonicacid optionally with the addition of copper(II) or cobalt(II) salts,such as, e.g., copper(II) sulfate, is preferred.

Step h (A-VIII

A-IX):

Protection of the two alcohol functions of 1,3-diol in A-VIII ispossible under acid catalysis by direct ketalization with a carbonylcompound of general formula R^(15a)—CO—R^(15b), or by reketalizationwith a ketal of general formulas R^(15a)—C(OC₂H₅)₂—R^(15b),R^(15a)—C(OC₂H₄)₂—R^(15b), R^(15a)—C(OCH₂C(CH₃)₂CH₂O)—R^(15b), in whichin each case R^(15a) and R^(15b) have the above-indicated meanings.Reketalization preferably with 2,2-dimethoxypropane is preferred. Asacids, the acids already mentioned under step f) are suitable, and theuse of camphorsulfonic acid is preferred.

Step i (A-IX

A-X):

Protective group PG⁵ introduced under step d) is now cleaved accordingto the process that is known to one skilled in the art. This is a silylether, thus suitable for the cleavage are the reaction with fluorides,such as, for example, tetrabutylammonium fluoride, hydrogenfluoride-pyridine complex, potassium fluoride or the use of dilutemineral acids, the use of catalytic quantities of acids, such as, e.g.,para-toluenesulfonic acid, para-toluenesulfonic acid-pyridinium salt,camphorsulfonic acid in alcoholic solutions, preferably in ethanol orisopropanol.

Step k (A-X

A-XI):

The oxidation of the primary alcohol in A-X to aldehyde is carried outaccording to the methods that are known to one skilled in the art. Forexample, oxidation with pyridinium chlorochromate, pyridiniumdichromate, chromium trioxide-pyridine complex, oxidation according toSwern or related methods, e.g., with use of oxalyl chloride in dimethylsulfoxide, the use of Dess-Martin periodinane, the use of nitrogenoxides, such as, e.g., N-methyl-morpholino-N-oxide in the presence ofsuitable catalysts, such as, e.g., tetrapropylammonium perruthenate ininert solvents, can be mentioned. Preferred is the oxidation accordingto Swern, as well as with N-methyl-morpholino-N-oxide usingtetrapropylammonium perruthenate.

Step l (A-XI

A-XII):

The reaction of aldehydes A-XI to alcohols of formula A-XII is carriedout with organometallic compounds of general formula M-CHR^(2a′)R^(2b′),in which M stands for an alkali metal, preferably lithium or a divalentmetal MX, in which X represents a halogen, and radicals R^(2a′) andR^(2b′) in each case have the above-mentioned meanings. As a divalentmetal, magnesium and zinc are preferred; as halogen X, chlorine, bromineand iodine are preferred.

Step m (A-XII

A-XIII):

Oxidation of the secondary alcohol in A-XII to ketone A-XIII is carriedout according to the conditions that are mentioned under step k).Oxidation with N-methyl-morpholino-N-oxide with use oftetrapropylammonium perruthenate is preferred.

Step n (A-XIII

A-XIV):

If R^(2a′) in A-XIII is equal to hydrogen, the possibility exists ofintroducing for this purpose a second radical R^(2a′), which has theabove-mentioned meanings, excluding hydrogen. For this purpose, ketonein A-XIII is introduced into the enolate with use of strong bases, suchas, e.g., lithium diisopropylamide, and reacted with a compound ofgeneral formula X-R^(2a′), in which X represents a halogen. As halogenX, chlorine, bromine and iodine are preferred.

The previously described path can also be used to synthesizeC1-C6-epothilone components, which on C-1 contain a carboxylic acid ortheir esters (R¹³═CO₂R^(13b) in A).

The synthesis of component A-XXII is described in Diagram 2 below in theexample of intermediate stage A-V that is derived fromD-(−)-pantolactone. The corresponding enantiomer compounds ent-A-V toent-A-XXVII in A-V to A-XXVII are obtained from L-(+)-pantolactone, andthe corresponding racemic compounds rac-A-V to rac-A-XXVII are obtainedfrom racemic DL-pantolactone:

Step o (A-V

A-XV):

Oxidation of the primary alcohol in A-V to aldehyde A-XV is carried outaccording to the conditions that are mentioned under step k). Theoxidation process according to Swern is preferred.

Step p (A-XV

A-XVI):

The reaction of aldehydes A-XV to alcohols of formula A-XVI is carriedout with organometallic compounds of general formula M-CHR^(2a′)R^(2b′),in which M stands for an alkali metal, preferably lithium or a divalentmetal MX, in which X represents a halogen, and radicals R^(2a′) andR^(2b′) in each case have the above-mentioned meanings. As a divalentmetal, magnesium and zinc are preferred; as halogen X, chlorine, bromineand iodine are preferred.

Step q (A-XVI

A-XVII):

Water is added to the double bond in A-XVI in an anti-Markovnikovorientation. For this purpose, the processes that are described under e)are suitable.

Step r (A-XVII

A-XVIII):

The free hydroxy group in A-XVII is protected according to the methodsthat are known to one skilled in the art. As protective group PG⁶, theprotective groups that are known to one skilled in the art, as werealready mentioned above for PG⁴ in step a (A-II

A-III), are suitable.

Preferred are those protective groups that can be cleaved under basic orhydrogenolytic reaction conditions, such as, e.g., benzyl,para-nitrobenzyl, acetyl, propionyl, butyryl, benzoyl radicals.Especially preferred is the benzoyl radical.

Step s (A-XVIII

A-XIX):

Oxidation of the secondary alcohol in A-XVII to ketone A-XIX is carriedout according to the conditions that are mentioned under step k).Preferred is oxidation with N-methyl-morpholino-N-oxide with use oftetrapropylammonium perruthenate.

Step t (A-XIX

A-XX):

Protective group PG⁶ in XIX is now selectively cleaved. This is ahydrogenolytically cleavable protective group, thus it is preferablyhydrogenated in the presence of palladium or platinum catalysts in inertsolvents, such as, for example, ethyl acetate or ethanol. This is abasically cleavable protective group, thus, saponification withcarbonates in alcoholic solution, such as, e.g., potassium carbinonatein methanol, saponification with aqueous solutions of alkali hydroxides,such as, e.g., lithium hydroxide or sodium hydroxide, are preferablyused while employing organic, water-miscible solvents, such as, e.g.,methanol, ethanol, tetrahydrofuran or dioxane.

Step u (A-XVII

A-XXI):

Oxidation of alcohols in A-XVII to ketoaldehyde A-XXI is carried outaccording to the conditions that are mentioned under step k). Preferredis oxidation with N-methyl-morpholino-N-oxide with use oftetrapropylammonium perruthenate and the method according to Swern.

Step v (A-XX

A-XXI):

Oxidation of primary alcohol in A-XX to ketoaldehyde A-XXI is carriedout according to the conditions that are mentioned under step k).Preferred is oxidation with N-methyl-morpholino-N-oxide with use oftetrapropylammonium perruthenate.

Step w (A-XXI

A-XXII):

Oxidation of the aldehyde in A-XXI to carboxylic acid A-XXII(R^(13b)=hydrogen) is carried out according to the methods that areknown to one skilled in the art. For example, the oxidation according toJones, oxidation with potassium permanganate, for example in an aqueoussystem that consists of tert-butanol and sodium dihydrogen phosphate,oxidation with sodium chlorite in aqueous tert-butanol optionally in thepresence of a chlorine trap, such as, e.g., 2-methyl-2-butene, can bementioned.

Oxidation of the aldehyde in A-XXI to ester A-XXII, in which R^(13b) hasthe above-mentioned meanings and is unequal to hydrogen, can be carriedout, for example, with pyridinium dichromate and the desired alcoholHO—R^(13b) in an inert solvent, such as, e.g., dimethylformamide.

Step x (A-VII

A-XXIII):

Oxidation of the primary alcohol in A-VII to aldehyde A-XXIII is carriedout according to the conditions that are mentioned under step k).Preferred is oxidation with N-methyl-morpholino-N-oxide with use oftetrapropylammonium perruthenate as well as the method according toSwern.

Step y (A-XXIII

A-XXIV):

Oxidation of aldehyde A-XXIII to carboxylic acid or its esters A-XXIV iscarried out according to the conditions already described under w).

Step z (A-XXIV

A-XXV):

Protective group PG⁵ introduced under step d) is cleaved as describedunder step i.

Step aa (A-XXV

A-XXVI):

Oxidation of the primary alcohol in A-XXV to aldehyde A-XXVI is carriedout according to the conditions that are mentioned under step k).Preferred is oxidation with N-methyl-morpholino-N-oxide with use oftetrabutylammonium perruthenate as well as the method according toSwern.

Step ab (A-XXVI

A-XXVII):

The reaction of aldehyde A-XXVI to alcohols of formula A-XXVII iscarried out according to the conditions that are mentioned under stepl).

Step ac (A-XXVII

A-XXII):

Oxidation of the secondary alcohol in A-XXVII to ketone A-XXII iscarried out according to the conditions that are mentioned under stepk). Preferred is oxidation with N-methyl-morpholino-N-oxide with use oftetrapropylammonium perruthenate.

The compounds of formula A, in which R^(1a′) and R^(1b′) all can havethe meanings that are indicated in general formula A can also beproduced from inexpensive or readily available malonic acid dialkylesters in an efficient way with high optical purity.

The synthesis is described in diagram 3 below:

Step ad (A-XXVIII

A-XXIX):

Correspondingly substituted malonic acid ester derivatives A-XXVIII,which are either commercially available or can be produced according tothe processes that are known to one skilled in the art from malonicacids or their alkyl esters, are reduced to diols A-XXIX. For thispurpose, the reducing agents that are known to one skilled in the art,such as, e.g., diisobutylaluminum hydride, and complex metal hydrides,such as, e.g., lithium aluminum hydride, are suitable.

Step ae (A-XXIX

A-XXX):

A free hydroxyl group in A-XXIX is selectively protected according tothe methods that are known to one skilled in the art. As protectivegroup PG⁷, the protective groups that are known to one skilled in theart, as were already mentioned above for PG⁴ in step a (A-II

A-III), are suitable.

Preferred are silicon-containing protective groups.

Step af (A-XXX

A-XXXI):

Oxidation of the remaining, primary hydroxyl group in A-XXX to aldehydeA-XXXI is carried out according to the conditions that are mentionedunder step k).

Preferred is oxidation with N-methyl-morpholino-N-oxide with use oftetrapropylammonium perruthenate, the use of pyridinium chlorochromate,pyridinium dichromate as well as the method according to Swern.

Step ag (A-XXXI

A-XXXII):

Aldehydes A-XXXI are reacted with an ester of acetic acid chG¹OC(O)CH₃,in which chG¹ means a chiral auxiliary group, in terms of an aldolreaction. Compounds chG¹OC(O)CH₃ are used in optically pure form in thealdol reaction. The type of chiral auxiliary group determines whetherthe aldol reaction proceeds with high diastereoselectivity or yields adiastereomer mixture that can be separated with physical methods. Asurvey on comparable diastereoselective aldol reactions is found inAngew. Chem. 99 (1987), 24-37. As chiral auxiliary groups chG¹-OH, forexample, optically pure 2-phenyl-cyclohexanol, pulegol,2-hydroxy-1,2,2-triphenylethanol, and 8-phenylmenthol are suitable.

Step ah (A-XXXII

A-XXXIII):

Diastereomer-pure compounds A-XXXII can then be converted according tothe process that is known to one skilled in the art by saponification ofthe ester unit with simultaneous release of reusable chiral auxiliarycomponent chG¹-OH into enantiomer-pure compounds of type A-XXXIII orent-A-XXXIII. For saponification, carbonates in alcoholic solution, suchas, e.g., potassium carbonate in methanol, aqueous solutions of alkalihydroxides, such as, e.g., lithium hydroxide or sodium hydroxide withuse of organic, water-miscible solvents, such as, e.g., methanol,ethanol, tetrahydrofuran or dioxane, are suitable.

Step ai (A-XXXII

A-VIII):

As an alternative to step ah, the chiral auxiliary group can also beremoved reductively. In this way, the enantiomer-pure compounds of typeA-VIII or ent-A-VIII are obtained. The reduction can be carried outaccording to the processes that are known to one skilled in the art. Asa reducing agent, e.g., diisobutylaluminum hydride and complex metalhydrides, such as, e.g., lithium aluminum hydride, are suitable.

Compounds A-VIII or ent-A-VIII can be converted as previously describedinto compounds of type A-XIII or ent-A-XIII. Correspondingly, compoundsof type A-XXXIII or ent-A-XXXIII can be converted into compounds of typeA-XXII or ent-A-XXII according to the processes described above.

As an alternative to the above-described method, the sequence can alsobe carried out without using chiral auxiliary group chG¹. In this way,racemic mixtures of compounds of type rac-A-VIII or rac-A-XXXIII arethen obtained via the corresponding, racemic precursors. These mixturescan in turn be separated according to the processes for racematecleavage, e.g., chromatography on chiral columns, known to one skilledin the art. The continuation of synthesis can also be carried out withracemic mixtures, however.

This invention thus also relates to a process for the production of thecompounds of general formula A, which is characterized in that

a) a pantolactone of general formula IIa or

b) a malonic acid dialkyl ester of general formula XXVIII is used as astarting product.

In addition, this invention thus relates to the new C1-C6-epothilonecomponents of general formula A′

in which

-   -   R² means CH₂OR^(2a), CHO, CO₂R^(2b), COX,    -   R^(2a), R^(2b) mean hydrogen, C₁-C₂₀ alkyl, aryl, C₇-C₂₀        aralkyl,    -   R³ means hydrogen, OR^(3a), X, OSO₂R^(3b),    -   R^(3a) means hydrogen or together with R^(2a) a —(CH₂)_(n) group        or a CR^(6a)R^(6b) group    -   R^(3b) means C₁-C₄ alkyl, aryl,    -   X means halogen,    -   n means 2 to 4,    -   R^(6a), R^(6b) are the same or different and mean C₁-C₈ alkyl,        C₆-C₁₀ aryl or together a —(CH₂)_(o) group,    -   o means 3 to 6,    -   R^(6a) additionally can assume the meaning of hydrogen,    -   R^(4a), R^(4b) are the same or different and mean hydrogen,        C₁-C₁₀ alkyl, C₇-C₂₀ aralkyl or together a —(CH₂)_(m) group,    -   m means 2 to 5,    -   R^(5a), R^(5b) are the same or different and mean hydrogen,        C₁-C₁₀ alkyl, C₇-C₂₀ aralkyl or together a —(CH₂)_(p) group,    -   p means 2 to 5,    -   R^(5c) means hydrogen,    -   including all stereoisomers and mixtures thereof, and

free hydroxyl groups can be etherified or esterified in R² and R³, freecarbonyl groups can be ketalized in A and R², converted into an enolether or reduced, and free acid groups in A can be converted into theirsalts with bases, excluding the compounds

P=TBS

It has also been found that synthesis components of general formula A″

in which

-   -   R³ means OR^(3a) and    -   R^(3a) means hydrogen or a protective group PG    -   R^(4a), R^(4b) are the same or different and mean hydrogen,        C₁-C₁₀-alkyl, C₇-C₂₀-aralkyl, or together a —(CH₂)_(m) group,    -   m means 2-5,    -   R^(5a), R^(5b) are the same or different and mean hydrogen,        C₁-C₁₀-alkyl, C₇-C₂₀-aralkyl, or together a —(CH₂)_(p) group,    -   p means 2-5,        including all stereoisomers and mixtures thereof, and        free carbonyl groups can be ketalized in I, can be produced        readily by reaction of a compound of general formula II

in which

X is a chlorine or bromine atom, and the 2-oxazolidinone ring has eithera (4R,5S) or a (4S,5R) conformation, with a compound of general formulaIII

in which

-   -   R^(4a), R^(4b) are the same or different and mean hydrogen,        C₁-C₁₀-alkyl, C₇-C₂₀-aralkyl, or together a —(CH₂)_(m) group,    -   m means 2-5,    -   R^(5a), R^(5b) are the same or different and mean hydrogen,        C₁-C₁₀-alkyl, C₇-C₂₀-aralkyl, or together a —(CH₂)_(p) group,    -   p means 2-5,        into a compound of general formula IV

in which

the 2-oxazolidinone ring (4R,5S) and the 3′-carbon atom have an Rconformation, or

the 2-oxazolidinone ring (4S,5R) and the 3′-carbon atom have an Sconformation,

as well as after the 3′-hydroxy group in IV is protected by a protectivegroup PG, by cleaving the oxazolidinone radical and optionally cleavingprotective group PG.

The reaction of a compound of general formula II with a compound ofgeneral formula III is accomplished after the compound of generalformula II is converted into a metallenolate by insertion of a metal ormetal salt into the carbon-halogen bond of the compound of generalformula II.

The metals or metal salts that are used generally include all metals ormetal salts that are known to one skilled in the art that are suitablefor a Reformatzky reaction (see, e.g., A. Furstner, Synthesis 1989, pp.571-590).

According to the invention, chromium(II) chloride is preferably used.

Upon cleavage, the oxazolidinone ring is recovered from the compounds ofgeneral formula IV almost quantitatively and without loss of opticalactivity.

Alkyl groups R^(4a), R^(4b), R^(5a), and R^(5b) are straight-chain orbranched-chain alkyl groups with 1 to a maximum of 10 carbon atoms, suchas, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, and decyl.

Alkyl groups R^(4a), R^(4b), R^(5a) and R^(5b) may be perfluorinated orsubstituted by 1-5 halogen atoms, hydroxy groups, C₁-C₄ alkoxy groups,and C₆-C₁₂ aryl groups (which can be substituted by 1-3 halogen atoms).

The aralkyl groups in R^(4a), R^(4b), R^(5a) and R^(5b) can contain upto 14 C atoms, preferably 6-10, in the ring and 1-8, preferably 1-4atoms in the alkyl chain. The aralkyl radicals that can be consideredinclude, for example, benzyl, phenylethyl, naphthylmethyl,naphthylethyl, furylmethyl, thienylethyl, and pyridylpropyl. The ringscan be substituted in one to three places by halogen, OH, O-alkyl, NH₂,CO₂H, CO₂-alkyl, —NO₂, —N₃, —CN, C₁-C₂₀-alkyl, C₁-C₂₀-acyl, andC₁-C₂₀-acyloxy groups.

Protective groups PG that can be considered include all radicals thatare known to one skilled in the art as such protective groups.Preference is given in this case to silyl-containing protective groups,such as, for example the trimethylsilyl, triethylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, andtriisopropylsilyl radicals.

A summary of protective groups is given in, e.g., “Protective Groups inOrganic Synthesis” by Theodora W. Green, John Wiley and Sons).

Halogen means fluorine, chlorine, bromine, and iodine.

The compounds of general formula II that are required for the processaccording to the invention can be obtained by acetylation of (4R,5S)- or(4S,5R)-4-methyl-5-phenyl-2-oxazolidinone with bromine orchlorine-acetyl chloride in the presence of a strong base, such as, forexample n-butyllithium.

The stereochemistry of the hydroxy group in position 3 is controlledlater by the selection of the chiral auxiliary.

The compounds of general formula III that are required for the processaccording to the invention can be obtained commercially or can easily bemanufactured.

To the extent that the compounds of general formula III are notavailable commercially, they can be manufactured using, for example, themethods that are indicated in Schemes 1 and 2.

By analogy with previously described methods, for instance those citedon page 2 of this application (Schinzer et al., Chem. Eur. J. 1996, 2,No. 11, pp. 1477-1482; Angew. Chem., 1997, 109, No. 5, pp. 543-544;Nicolaou et al.; Angew. Chem. 1997, 109, Nos. 1/2, pp. 170-172; Nature,Vol. 387, 1997, pp. 268-272; J. Am. Chem. Soc., Vol. 119, No. 34, 1997,pp. 7960-7973; J. Am. Chem. Soc., Vol. 119, No. 34, 1997, pp. 7974-7991;Angew. Chem. 1997, 109, No. 19, pp. 2181-2187), the components ofgeneral formula I that are produced according to this invention can beused for the synthesis of epothilone A and B, as well as in the C₁-C₆section of the epothilone framework that corresponds to modifiedepothilone derivatives.

The variability of the substituents that was required at the beginningof this document is thus achieved with the compounds of general formulaI.

A major advantage of the process according to the invention also lies inthe fact that the chiral auxiliary (4R,5S)- or(4S,5R)-4-methyl-5-phenyl-2-oxazolidinone that is used is easy torecover after it is cleaved from the protective compound of generalformula IV and can be reinserted into the synthesis process without lossof optical induction.

The components that are obtained in these ways, as well as theirenantiomers or mixtures of these enantiomers, are suitable foraldo-condensation with an epothilone component that at C-7 (epothilonenumbering system) carries a carbonyl function, as is the case with theabove-mentioned total syntheses of epothilone A and epothilone B.

Components A, their enantiomers or mixtures of these enantiomers arealso suitable for esterification with an epothilone component which atC-15 (epothilone numbering system) carries a hydroxy function, as is thecase with the above-mentioned total syntheses of epothilone A andepothilone B.

Representation of Partial Fragments B:

Step a (B-II

B-III):

A hydroxyl group in B-II is protected according to the methods that areknown to one skilled in the art. As protective group PG⁸, the protectivegroups that are known to one skilled in the art, as were alreadymentioned above for PG⁴ in step a (A-II ### A-III), are suitable.

Preferred are silicon-containing protective groups, which can be cleavedunder acid reaction conditions or use of fluoride, such as, e.g.,trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, tribenzylsilyl and triisopropylsilyl radicals.

Especially preferred is the tert-butyldimethylsilyl radical.

Step b (B-III

B-IV):

The free hydroxyl group in B-III is converted into a leaving group LGaccording to the methods that are known to one skilled in the art. Asleaving group LG, for example, halogens such as, e.g., bromine or iodineor alkyl- or aryl sulfonates, which are produced from the correspondingsulfonic acid halides or sulfonic acid anhydrides according to themethods that are known to one skilled in the art, are suitable.

As leaving group LG, the trifluoromethanesulfonate is preferred.

Step c (B-IV

B-VII):

Compound B-IV is alkylated with the enolate of a carbonyl compound ofgeneral formula B-V, in which chG² can be a single alkoxy group or elsea chiral auxiliary group according to the methods that are known to oneskilled in the art. The enolate is produced by action of stronger bases,such as, e.g., lithium diisopropylamide, lithium hexamethyldisilazane atlow temperatures. As chiral auxiliary group chG²-H (B-VI), chiralalcohols that can be produced in an optically pure and inexpensivemanner, such as, e.g., pulegol, 2-phenylcyclohexanol,2-hydroxy-1,2,2-triphenylethanol, 8-phenylmenthol or compounds thatcontain reactive NH-groups that can be produced in an optically pure andinexpensive manner, such as, e.g., amines, amino acids, lactams oroxazolidinones, are suitable. Preferred are oxazolidinones; especiallypreferred are the compounds of formulas B-VIa to B-VId. The absolutestereochemistry on the α-carbonylcarbon of the compound of generalformula B-VII is set by the selection of the respective antipodes. Inthis way, the compounds of general formulas B-VII to B-XVII or theirrespective enantiomers ent-B-VII to ent-B-XVII can be obtained in anenantiomer-pure manner. If an achiral alcohol, such as, e.g., ethanol,is used as chG²-H (B-VI), the racemic compounds rac-B-VII to rac-B-XVIIare obtained.

Step d (B-VII

B-VIII):

If group chG² represents one of the chiral auxiliary groups that arementioned under step c, the latter is recovered by reesterification ofB-VII in an alkyl ester of general formula B-VIII. The reesterificationis carried out according to the methods that are known to one skilled inthe art. Preferred is reesterification with simple alcohols, such as,e.g., methanol or ethanol in the presence of corresponding titanium(IV)alcoholates.

Step e (B-VIII

B-IX):

The ester in B-VIII is reduced to alcohol B-IX. As a reducing agent, thereducing agents that are known to one skilled in the art, such as, e.g.,aluminum hydrides, such as, e.g., lithium aluminum hydride ordiisobutylaluminum hydride, are suitable. The reaction is carried out inan inert solvent, such as, e.g., diethyl ether, tetrahydrofuran,toluene.

Step e′ (B-VII

B-IX):

As an alternative to steps d) and e), the carbonyl group in B-VII can bereduced immediately to the alcohols of general formula B-IX according tothe conditions that are mentioned under step e). Here, the chiralauxiliary component chG²-H can also be recovered.

Step f (B-IX

B-X):

The free hydroxyl group in B-IX is protected according to the methodsthat are known to one skilled in the art. As protective group PG⁹, theprotective groups that are known to one skilled in the art, as werealready mentioned above for PG⁴ in step a (A-II ### A-III), aresuitable.

Preferred are those protective groups that can be cleaved under acidicreaction conditions, such as, e.g., the methoxymethyl,tetrahydropyranyl, tetrahydrofuranyl, and trimethylsilyl radical.

Especially preferred is the tetrahydropyranyl radical.

Step g (B-X

B-XI):

Protective group PG⁸, which is introduced under step a), is now cleavedaccording to the processes that are known to one skilled in the art. Ifthis is a silyl ether, then the reaction with fluorides, such as, forexample, tetrabutylammonium fluoride, the hydrogen fluoride-pyridinecomplex, potassium fluoride or the use of dilute mineral acids, the useof catalytic quantities of acids, such as, e.g., para-toluenesulfonicacid, para-toluenesulfonic acid-pyridinium salt, camphorsulfonic acid inalcoholic solutions, preferably in ethanol or isopropanol, are suitablefor the cleavage.

Step h (B-XI

B-XII):

Oxidation of the primary alcohol in B-XI to the aldehyde of generalformula B-XII is carried out according to the processes that are knownto one skilled in the art. For example, oxidation with pyridiniumchlorochromate, pyridinium dichromate, chromium trioxide-pyridinecomplex, oxidation according to Swern or related methods, e.g., with useof oxalyl chloride in dimethyl sulfoxide, the use of Dess-Martinperiodinane, the use of nitrogen oxides, such as, e.g.,N-methyl-morpholino-N-oxide in the presence of suitable catalysts, suchas, e.g., tetrapropylammonium perruthenate in inert solvents, can bementioned. Preferred is the oxidation according to Swern, as well aswith N-methyl-morpholino-N-oxide with use of tetrapropylammoniumperruthenate.

Step i (B-XII

B-XIII):

The reaction of aldehyde B-XII to alcohols of general formula B-XIII iscarried out according to the methods that are known to one skilled inthe art with organometallic compounds of general formula M-R^(5′), inwhich M stands for an alkali metal, preferably lithium or a divalentmetal MX, in which X represents a halogen and radical R^(5′) has theabove-mentioned meaning. As a divalent metal, magnesium and zinc arepreferred; as halogen X, chlorine, bromine and iodine are preferred.

Step k (B-XIII

B-XIV):

Oxidation of alcohol B-XIII to the ketone of general formula B-XIV iscarried out according to the processes that are mentioned under h).Preferred is oxidation with N-methyl-morpholino-N-oxide with use oftetrapropylammonium perruthenate.

Step l (B-XIII

B-XV):

The hydroxyl group in B-XIII can be provided according to the processesthat are mentioned under a) with a protective group PG¹⁰. Preferred aresilicon-containing protective groups, which can be cleaved under acidicreaction conditions or use of fluoride, such as, e.g., thetrimethylsilyl, triethylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl radical.Especially preferred is the tert-butyldiphenylsilyl radical.

Step m (B-XV

B-XVI):

Protective group PG⁹, which is introduced under step f), is cleavedaccording to the processes that are described under step g).

Step n (B-XVI

B-XVII):

Oxidation of alcohol B-XVI to the aldehyde of general formula B-XVII iscarried out according to the processes that are mentioned under h).Preferred is oxidation according to Swern.

As an alternative, the compounds of general formula B-XIII can beproduced with the method that is described in Diagram 5.

Step o (B-XVIII

B-XIX):

Starting from ethyl acetate derivatives, which can be obtainedinexpensively, of general formula B-XVIII, in which R^(4a′) and R^(4b′)have the above-mentioned meanings, the ester enolate is produced byaction of strong bases, such as, e.g., lithium diisopropylamide, lithiumhexamethyldisilazane at low temperatures and reacted with3-halogen-1-propine, preferably 3-bromo-1-propine to compounds ofgeneral formula B-XIX.

Step p (B-XIX

B-XX):

The reduction of ester B-XIX to alcohol B-XX is carried out according tothe methods that are described under step e), preferably with use ofdiisobutylaluminum hydride.

Step q (B-XX

B-XXI):

The hydroxyl group in B-XX can be provided according to the conditionsthat are mentioned under a) with a protective group PG¹¹. Preferred aresilicon-containing protective groups, which can be cleaved under acidicreaction conditions or use of fluoride, such as, e.g., thetrimethylsilyl, triethylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, tribenzylsilyl-triisopropylsilyl radical.Especially preferred is the tert-butyldimethylsilyl radical.

Step r (B-XXI

B-XIII):

Acetylene B-XXI can be deprotonated according to the processes that areknown to one skilled in the art, and the acetylide that is obtained canbe reacted with carbonyl compounds of general formula B-XXII, in whichR^(5′) has the above-mentioned meaning, to an alcohol of general formulaXIII. For deprotonation, alkyl alkali compounds, such as, e.g.,butyllithium or other strong bases, such as, e.g., alkalihexamethyldisilazane or lithium diisopropylamide, are suitable.Preferred is n-butyllithium.

In the process that is described in Diagram 5, first the racemiccompounds rac-B-XIII are obtained. Optionally, steps rac-B-XIX orrac-B-XX that are passed through according to Diagram 6 offer thepossibility for chemical racemate cleavage and thus also access toenantiomer-pure compounds B-XX or ent-B-XX, if R^(4a′) is not identicalto R^(4b′).

Step s (rac-B-XIX

B-XIXa):

Racemic compound rac-B-XIX can be reesterified with a chiral alcoholchG³-OH that can be obtained in an optically pure manner according tothe methods that are known to one skilled in the art, for example theprocess that is mentioned under step d), to a mixture of diastereomericester B-XIXa and separated with simple, chromatographic methods. Aschiral alcohols, for example, pulegol, 2-phenylcyclohexanol,2-hydroxy-1,2,2-triphenylethanol, 8-phenylmethanol are suitable.

Step t (B-XIXa

B-XX and ent-B-XX):

Diastereomer-pure esters B-XIXa can be reduced in each case to alcoholsB-XX or ent-B-XX according to the process that is described under stepe, whereby auxiliary component chG³-OH that is described under step scan be recovered.

Step u (rac-B-XX

B-XXa):

Racemic compound rac-B-XX can be reacted with a chiral acid chG⁴-CO₂Hthat can be obtained in an optically pure manner, its esters, anhydrideor acid halide, according to the methods that are known to one skilledin the art, to a mixture of the diastereomer ester XXa and separatedwith simple chromatographic methods. As chiral acids, for example, malicacid, tartaric acid or their derivatives are suitable.

Step v (B-XXa

B-XX and ent-B-XX):

Diastereomer-pure esters B-XXa can be reduced in each case to alcoholsB-XX or ent-B-XX according to the process that is described under stepe, or saponified according to the methods that are known to one skilledin the art, whereby in the last-mentioned case, auxiliary componentchG⁴-CO₂H that is described under step u can be recovered.

Representation of Partial Fragments C:

It is known that the compound of formula

(TBDMS stands for a tert-butyldimethylsilyl radical) can be used for thesynthesis of the C13-C16 fragment (epothilone numbering system) ofepothilone A (Schinzer et al. Chem. Eur. J. 1996, 2, No. 1, 1477-1482).The synthesis that is described by Schinzer et al. introduces therequired chirality via a kinetic racemate cleavage according toSharpless. A necessary chromatographic separation, an inadequateenantiomer excess (80%) and a small overall yield disqualify this methodfor an industrial synthesis, which requires high yields and high opticalpurity of the synthesis products.

It is further known that the above-mentioned synthesis component can beconverted with the phosphonate of formula

by Wittig reaction into a compound of formula

which can then be used for the introduction of the C13-C20 fragment forepothilone synthesis.

Partial fragments of formula C can be produced from malic acid, whichcan be obtained in an inexpensive, reasonably-priced manner, in anefficient way with high optical purity (>99.5%).

The synthesis is described in Diagram 7 below in the example ofL-(−)-malic acid (C-I). Starting from D(+)-malic acid (ent-C-I), thecorresponding enantiomeric compounds (ent-C-II to ent-C-XI) areobtained, and starting from racemic malic acid (rac-C-I), thecorresponding racemic compounds (rac-C-II to rac-C-XI) are obtained).

Step a (malic acid C-I

C-II):

L-(−)-Malic acid is converted into hydroxylactone C-II according to aprocess that is known in the literature (Liebigs Ann. Chem. 1993,1273-1278).

Step b (C-II

C-III):

The free hydroxy group in compound C-II is protected according to themethods that are known to one skilled in the art. As protective groupPG¹², the protective groups that are known to one skilled in the art, aswere already mentioned above for PG⁴ in step a (A-II ### A-III), aresuitable.

Preferred are those protective groups that can be cleaved under theaction of fluoride, but are stable under weakly acid reactionconditions, such as, e.g., the tert-butyldiphenylsilyl,tert-butyldimethylsilyl or triisopropylsilyl radical.

Especially preferred are the tert-butyldiphenylsilyl radical and thetert-butyldimethylsilyl radical.

Step c (C-III

C-IV):

Lactone C-III is reduced to lactol C-IV according to the methods thatare known to one skilled in the art. As reducing agents, aluminumhydrides that are modified in their reactivity, such as, e.g.,diisobutylaluminum hydride, are suitable. The reaction is carried out inan inert solvent, such as, e.g., toluene, preferably at low temperatures(−20 to −100° C.).

Step d (C-IV

C-V):

The reaction of lactol C-IV to compounds of formula C-V is carried outwith organometallic compounds of general formula M-R^(8′), in which Mstands for an alkali metal, preferably lithium, or a divalent metal MX,in which X represents a halogen, and R^(8′) has the above-mentionedmeanings. As a divalent metal, magnesium and zinc are preferred, and ashalogen X, chlorine, bromine and iodine are preferred.

Step e (C-V

C-VI):

The primary hydroxyl group in compound C-V is protected in a selectivemanner relative to the secondary hydroxyl group according to the methodsthat are known to one skilled in the art.

The secondary hydroxy group is optionally then protected also accordingto the methods that are familiar to one skilled in the art.

As protective groups PG¹³ and PG^(VI″), the protective groups that areknown to one skilled in the art, as were already mentioned above for PG⁴in step a (A-II ### A-III), are suitable.

Preferred are those protective groups that can be cleaved under weaklyacidic reaction conditions in a selective manner in the presence ofprotective group PG10, which is introduced from component A into thesynthesis of the compounds of general formula I, such as, e.g., thetrimethylsilyl, triethylsilyl, tert-butyldimethylsilyl radical.

Especially preferred is the tert-butyldimethylsilyl radical.

Step f (C-VI

C-VII):

Oxidation of the secondary alcohol in C-VI to ketone C-VII is carriedout according to the methods that are known to one skilled in the art.For example, oxidation with pyridinium chlorochromate, pyridiniumdichromate, chromium trioxide-pyridine complex, oxidation according toSwern or related methods, e.g., with use of oxalyl chloride in dimethylsulfoxide, the use of Dess-Martin periodinane, the use of nitrogenoxides, such as, e.g., N-methyl-morpholino-N-oxide in the presence ofsuitable catalysts, such as, e.g., tetrapropylammonium perruthenate ininert solvents, can be mentioned. Preferred is oxidation according toSwern.

Step g (C-VII

C-VIII):

For compounds in which U is equal to CR10′R11′, this grouping isestablished according to the processes that are known to one skilled inthe art. For this purpose, methods such as, e.g., the Wittig orWittig/Horner reaction, the addition of an organometallic compoundMCHR10′R11′ with dehydration, are suitable. Preferred is the Wittig andWittig/Horner reaction with use of phosphonium halides of typeCR10′R11′P(Ph)3⁺Hal⁻ or phosphonates of type CR10′R11′P(O)(Oalkyl)2 withPh equal to phenyl, R10′, R11′ and halogen in the already mentionedconditions with strong bases, such as, e.g., n-butyllithium,potassium-tert-butanolate, sodium ethanolate, sodiumhexamethyldisilazane; n-butyllithium is preferred as a base.

For compounds in which U represents two alkoxy groups OR²³ or a C₂-C₁₀alkylene-α,ω-dioxy group, the ketone is ketalized under acid catalysisaccording to the methods that are known to one skilled in the art, forexample, with use of an alcohol HOR²³ or a C₂-C₁₀ alkylene-α,ω-diol.

Step h (C-VIII

C-IX):

Protective group PG¹³ that is introduced under e is now selectivelycleaved in the presence of PG¹² according to the processes that areknown to one skilled in the art. If this a protective group that can becleaved acidically, then cleavage is carried out preferably under weaklyacidic conditions, such as, e.g., by reaction with dilute organic acidsin inert solvent. Preferred is acetic acid.

Step i (C-IX

C-X):

The free primary hydroxyl group is optionally converted into a halideaccording to the processes that are known to one skilled in the art.Preferred halides are chlorine, but especially bromine and iodine. Thesubstitution of the hydroxyl group for a bromine can be carried outusing, e.g., triphenylphosphine/tetrabromomethane, but also according toany other process that is known to one skilled in the art. Theestablishment of an iodine atom can be done from the bromide bysubstitution, e.g., according to Finkelstein with sodium iodide inacetone. Direct conversion of the hydroxyl group into iodide is alsopossible, e.g., with use of elementary iodine, imidazole andtriphenylphosphine in dichloromethane.

If U ultimately is to stand for H/OR⁹ with R⁹ in the meaning of ahydrogen atom, the conversion of the primary hydroxy group into ahalogen atom is performed in the stage of compound C-VI′ according toselective reaction of the primary hydroxy group.

Step k (C-X

C-XI):

If the linkage of the C13-C16 unit with the 12-position of theepothilone radical or of the epothilone fragments, e.g., a C7-C12 unit,is to be carried out by Wittig reaction, as described in, e.g., NatureVol. 387, 268-272 (1997), the triphenyl-phosphonium-halides (R²¹=P(Ph)₃⁺Hal⁻), alkyl or aryl phosphonates (R²¹=P(O)(OQ)₂) or phosphine oxides(R²¹=P(O)Ph₂) of type C-XI are produced starting from halides C-Xaccording to the processes that are known to one skilled in the art. Inthis case, Ph means phenyl; Hal stands for F, Cl, Br or I, and Q is aC₁-C₁₀ alkyl or phenyl radical.

For the production of phosphonium salts, e.g., the reaction of thecorresponding halides with triphenylphosphine in solvents such astoluene or benzene is suitable.

The production of phosphonates can be carried out, e.g;, by reaction ofhalides C-X with a metallized dialkylphosphite. The metallization isusually carried out with strong bases, such as, e.g., butyllithium.

The production of the phosphine oxides can be carried out, e.g., byreaction of halides C-X with metallized diphenylphosphine and subsequentoxidation. For metallization, strong bases such as butyllithium are alsosuitable. The subsequent oxidation to phosphine oxide can then becarried out with, e.g., dilute aqueous hydrogen peroxide solution.

It has been found that, surprisingly enough, compounds of formula C′ canbe produced from enantiomer-pure malic acid, which can be obtained in aninexpensive, reasonably-priced manner, in an efficient way with highoptical purity (>99.5%), although basically the possibility for completeor partial racemization would exist in the described process accordingto the invention.

As mentioned above, the known process supplies those compounds in whichR¹ is a methyl group, R² is a tert-butyldimethylsilyl or benzyl radical,R³ is an O-tert-butyldimethylsilyl radical and X is an oxygen atom or a(2-methylthiazol-4-yl)methylene radical, only in an optical purity ofabout 80%.

In addition, the chemical yields of the process according to theinvention are considerably higher than the yields that are indicated inthe processes that are described by Schinzer et al. For example, theyield of(3S)-5-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-pentanone,produced according to the process of the-invention and starting fromL-(−)-malic acid with 26.5% is almost twice as high as the yield that isindicated by Schinzer et al. in the production of(3S)-3-benzyloxy-5-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-2-pentanone(14.35%; Chem. Eur. J. 1996, 2, No. 11, 1477-1482) or achieved in theproduction of(3S)-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-5-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-2-pentanone(20.58%; Angew. Chem. 1997, 109, No. 5, 543-544).

This comparison is based on the yields that are indicated in theabove-mentioned bibliographic references, whereby—as already mentionedabove—it is to be taken into consideration that the compounds that areobtained according to the known processes do not accumulate in anenantiomer-pure manner, such that the actual yield of theenantiomer-pure compound i question is lower, and an additionalpurification step in this or a later process stage is necessary forobtaining an enantiomer-pure compound.

Moreover, the process according to the invention makes possible a verywide variation of substituents in this C13-C16 component.

This invention thus relates to a process for the production of thecompounds of general formula C′, which is characterized in thatL-(−)-malic acid, D(+)-malic acid or racemic malic acid is used as astarting product.

Optically pure D-(+)- or L-(−)-malic acid is preferably used.

The invention also relates to the intermediate compounds of generalformulas V, VI and VI′ (combined below as VI″) that occur in the process

in which

R¹, PG¹ and R⁵ have the meaning that is indicated in general formula C′and

PG^(2+H) stands for a hydrogen atom or a protective group PG².

These compounds are produced according to the invention in that anorganometal compound of general formulaR¹Yin which

-   -   R¹ has the meaning that is indicated in general formula C′, and    -   Y stands for an alkali metal atom or MZ, whereby M is a divalent        metal atom and Z is a halogen atom,        is added to a compound of general Formula IV

in which

PG¹ has the meaning that is indicated in general Formula C, while thelactol ring is opened.

Lithium is preferred as an alkali atom.

In the case of MZ, magnesium and zinc are preferred for the divalentmetal atom; as a halogen atom, primarily chlorine, bromine and iodineare considered.

In addition, this invention relates to the new C13-C16 epothilonecomponents of general formula C

in which

-   -   R¹ means hydrogen, C₁-C₂₀ alkyl, aryl, C₇-C₂₀ aralkyl, which can        all be substituted,    -   R² means hydrogen or a protective group PG¹,    -   R³ means a hydroxy group, halogen, a protected hydroxy group        OPG², a phosphonium halide radical PPh₃ ⁺Hal⁻ (Ph=phenyl; Hal=F,        Cl, Br, I), a phosphonate radical P(O)(OQ)₂ (Q=C₁-C₁₀ alkyl or        phenyl) or a phosphine oxide radical P(O)Ph₂ (Ph=phenyl),    -   X means an oxygen atom, two alkoxy groups OR⁴, a C₂-C₁₀        alkylene-α,ω-dioxy group, which can be straight-chain or        branched, H/OR⁵ or a grouping CR⁶R⁷,        -   whereby        -   R⁴ stands for a C₁-C₂₀ alkyl radical,        -   R⁵ stands for hydrogen or a protective group PG³,        -   R⁶, R⁷ are the same or different and stand for hydrogen, a            C₁-C₂₀ alkyl, aryl, C₇-C₂₀ aralkyl radical or R⁶ and R⁷            together with the methylene carbon atom together stand for a            5- to 7-membered carbocyclic ring,            whereby not simultaneously    -   R¹ can be a methyl group, R² can be a tert-butyldimethylsilyl or        benzyl radical, R³ can be an O-tert-butyldimethylsilyl radical        and X can be a (2-methylthiazol-4-yl)methylene radical or R¹ can        be a methyl group, R² can be a tert-butyldimethylsilyl radical,        R³ can be a triphenylphosphonium iodide radical and X can be a        (2-methylthiazol-4-yl)methylene radical.

The first disclaimer excludes those compounds that were already producedby Schinzer et al. according to a process different from the processaccording to the invention (Chem. Eur. J. 1996, 2, No. 11, 1477-1482 andAngew. Chem. 1997, 109, No. 5, 543-544).

The second disclaimer takes into consideration the(5E,3S)-[3-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-en-1-yl]-triphenylphosphoniumiodide that is mentioned by K. C. Nicolaou et al. in Nature, Vol. 387,1997, 268-272.

For the more detailed explanation of substituents R¹, R⁴, R⁶, R⁷, PG¹,PG² and PG³ that occur in the compounds of general formula C, thestatements that are made above for the substituents of general formulaC′ hold true.

According to the invention, those compounds of general formula C arepreferred, in which

-   -   R¹ stands for a hydrogen atom, an optionally substituted C₁-C₄        alkyl radical, a phenyl radical that is optionally substituted        with 1 to 3 radicals, selected from the group of substituents        halogen, free hydroxy group or protected hydroxy group OPG⁴,        C₁-C₄ alkyl, azido, nitro, nitrile and amino (NH₂), and/or    -   X stands for an oxygen atom, and/or    -   the aryl radical that stands for R⁶ and/or R⁷ stands for a        phenyl radical that is optionally substituted with 1 to 3        radicals, selected from the group of substituents halogen, free        hydroxy group or protected hydroxy group OPG⁵, CO₂H, CO₂-alkyl,        C₁-C₄ alkyl, azido, nitro, nitrile, amino (NH₂), or for a 5- or        6-membered heteroaryl radical that is optionally substituted        with 1 to 2 C₁-C₄ alkyl radicals,        -   especially for a substituent that is selected from the group            2-, 3-furanyl; 2-, 3-, 4-pyridinyl; 2-, 4-, 5-thiazolyl; 2-,            4- and 5-imidazolyl radical, which optionally is substituted            by 1 or 2 C₁-C₄ alkyl radicals, and/or    -   PG¹, PG² and PG³ are selected from the group of substituents        methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl,        tetrahydrofuranyl, trimethylsilyl, triethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl,        tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl,        para-methoxybenzyl, acetyl, propionyl, butyryl and benzoyl        radicals,    -   in particular PG¹ is a tert-butyldiphenylsilyl,        tert-butyldimethylsilyl or triisopropylsilyl radical, and

in particular PG² is a tert-butyldimethylsilyl, acetyl, benzoyl, benzyl,tetrahydropyranyl radical.

As protective groups PG⁴ and PG⁵, all protective groups that areindicated above for PG¹, PG² and PG³ are suitable.

Representation of partial fragments ABC and their cyclization to I:

Partial fragments of general formula AB

in which R^(1a′), R^(1b′), R^(2a′), R^(2b′), R³, R^(4a), R^(4b), R⁵,R¹³, R¹⁴, D, E, V and Z have the meanings already mentioned, and PG¹⁴represents a hydrogen atom or a protective group PG, are obtained frompreviously described fragments A and B according to the process that isshown in Diagram 8.

Step a (A+B

AB):

Compound B, in which W has the meaning of an oxygen atom and optionallypresent additional carbonyl groups are protected, is alkylated with theenolate of a carbonyl compound of general formula A. The enolate isproduced by action of strong bases, such as, e.g., lithiumdiisopropylamide, lithium hexamethyldisilazane, at low temperatures.

Partial fragments of general formula ABC

in which R^(1a′), R^(1b′), R^(2a′), R^(2b′), R³, R^(4a), R^(4b), R⁵, R⁶,R⁷, R⁸, R¹³, R¹⁴, D, E, U and Z have the already mentioned meanings, areobtained from previously described fragments AB and C according to theprocess that is shown in Diagram 9.

Step b (AB+C

ABC):

Compound C, in which R²¹ has the meaning of a Wittig salt, andoptionally present additional carbonyl groups are protected, isdeprotonated by a suitable base, such as, e.g., n-butyllithium, lithiumdiisopropyl amide, potassium tert-butanolate, sodium orlithium-hexamethyldisilazide and reacted with a compound AB, in which Vhas the meaning of an oxygen atom.

Step c (ABC

1):

Compounds ABC, in which R¹³ represents a carboxylic acid CO₂H and R²⁰represents a hydrogen atom, are reacted according to the methods thatare known to one skilled in the art for the formation of largemacrolides to compounds of formula I, in which Y has the meaning of anoxygen atom. Preferred is the method that is described in “Reagents forOrganic Synthesis, Vol. 16, p. 353” with use of 2,4,6-trichlorobenzoicacid chloride and suitable bases, such as, e.g., triethylamine,4-dimethylaminopyridine, sodium hydride.

Step d (ABC

1):

Compounds ABC, in which R¹³ represents a group CH₂OH and R²⁰ representsa hydrogen atom, can be reacted preferably with use oftriphenylphosphine and azodiesters, such as, for example,azodicarboxylic acid diethyl ester, to compounds of formula I, in whichY has the meaning of two hydrogen atoms.

Compounds ABC, in which R¹³ represents a group CH₂OSO₂ alkyl or CH₂OSO₂aryl or CH₂OSO₂ aralkyl and R²⁰ represents a hydrogen atom, can becyclized to compounds of formula I, in which Y has the meaning of twohydrogen atoms, after deprotonation with suitable bases, such as, forexample, sodium hydride, n-butyllithium, 4-dimethylaminopyridine, Hunigbase, alkylhexamethyldisilazanes.

The flexible functionalization of described components A, B, and C alsoensures a linkage sequence that deviates from the above-describedprocess and that leads to components ABC. These processes are listed inthe following table:

Linkage Methods a Possible Linkages to e Prerequisites A + B → A − B a:Aldol (see Z = W = oxygen Diagram 8) B + C → B − C b: Wittig U = oxygenand R²¹ = (analogously to Wittig salt or Diagram 9) phosphine oxide ore: McMurry phosphonate U = V = oxygen A + C → A − C c: EsterificationR¹³ = CO₂R^(13b) or (e.g., 2,4,6- COHal and trichlorobenzoyl R²⁰ =hydrogen chloride/4- R¹³ = CH₂OH and R²⁰ = dimethylamino- hydrogen orSO₂-alkyl or pyridine) SO₂-aryl or d: etherification SO₂-aralkyl (e.g.,Mitsunobu)

According to these processes, components A, B and C, as indicated inDiagram 10, can be linked:

Free hydroxyl groups in I, A, B, C, AB, ABC can be further functionallymodified by etherification or esterification, free carbonyl groups byketalization, enol ether formation or reduction.

The invention relates to all stereoisomers of these compounds and alsotheir mixtures.

Biological Actions and Applications of the New Derivatives:

The new compounds of formula I are valuable pharmaceutical agents. Theyinteract with tubulin by stabilizing microtubuli that are formed and arethus able to influence the cell-splitting in a phase-specific manner.This relates mainly to quick-growing, neoplastic cells, whose growth islargely unaffected by intercellular regulating mechanisms. Activeingredients of this type are in principle suitable for treatingmalignant tumors. As applications, there can be mentioned, for example,the treatment of ovarian, stomach, colon, adeno-, breast, lung, head andneck carcinomas, malignant melanoma, acute lymphocytic and myelocyticleukemia. The compounds according to the invention are suitable owing totheir properties basically for anti-angiogenesis therapy as well as fortreatment of chronic inflammatory diseases, such as, for example,psoriasis or arthritis. To avoid uncontrolled proliferation of cells andfor better compatibility of medical implants, they can basically beapplied or introduced into the polymer materials that are used for thispurpose. The compounds according to the invention can be used alone orto achieve additive or synergistic actions in combination with otherprinciples and classes of substances that can be used in tumor therapy.

As examples, there can be mentioned the combination with

-   -   Platinum complexes, such as, e.g., cis-platinum, carboplatinum,    -   intercalating substances, e.g., from the class of        anthracyclines, such as, e.g., doxorubicin or from the class of        anthrapyrazoles, such as, e.g., Cl-941,    -   substances that interact with tubulin, e.g., from the class of        vinca-alkaloids, such as, e.g., vincristine, vinblastine or from        the class of taxanes, such as, e.g., taxol, taxotere or from the        class of macrolides, such as, e.g., rhizoxin or other compounds,        such as, e.g., colchicine, combretastatin A-4,    -   DNA topoisomerase inhibitors, such as, e.g., camptothecin,        etoposide, topotecan, teniposide,    -   folate- or pyrimidine-antimetabolites, such as, e.g.,        lometrexol, gemcitubin,    -   DNA-alkylating compounds, such as, e.g., adozelesin, dystamycin        A,    -   inhibitors of growth factors (e.g., of PDGF, EGF, TGFb, EGF),        such as, e.g., somatostatin, suramin, bombesin antagonists,    -   inhibitors of protein tyrosine kinases or protein kinases A or        C, such as, e.g., erbstatin, genistein, staurosporine,        ilmofosine, 8-Cl-cAMP,    -   antihormones from the class of antigestagens, such as, e.g.,        mifepristone, onapristone or from the class of antiestrogens,        such as, e.g., tamoxifen or from the class of antiandrogens,        such as, e.g., cyproterone acetate,    -   metastases-inhibiting compounds, e.g., from the class of        eicosanoids, such as, e.g., PGl₂, PGE₁, 6-oxo-PGE₁ as well as        their more stable derivatives (e.g., iloprost, cicaprost,        misoprostol),    -   inhibitory, oncogenic RAS proteins, which influence the mitotic        signal transduction, such as, for example, inhibitors of the        farnesyl-protein-transferase,    -   natural or synthetically produced antibodies, which are directed        against factors or their receptors, which promote tumor growth,        such as, for example, the erbB2 antibodies.

The invention also relates to pharmaceutical agents that are based onpharmaceutically compatible compounds, i.e., compounds of generalformula I that are nontoxic in the doses used, optionally together withcommonly used adjuvants and vehicles.

According to methods of galenicals that are known in the art, thecompounds according to the invention can be processed intopharmaceutical preparations for enteral, percutaneous, parenteral orlocal administration. They can be administered in the form of tablets,coated tablets, gel capsules, granulates, suppositories, implants,injectable, sterile, aqueous or oily solutions, suspensions oremulsions, ointments, creams and gels.

In this case, the active ingredient or ingredients can be mixed with theadjuvants that are commonly used in galenicals, such as, e.g., gumarabic, talc, starch, mannitol, methyl cellulose, lactose, surfactantssuch as Tweens or Myrj, magnesium stearate, aqueous or non-aqueousvehicles, paraffin derivatives, cleaning agents, dispersing agents,emulsifiers, preservatives and flavoring substances for taste correction(e.g., ethereal oils).

The invention thus also relates to pharmaceutical compositions, which asactive ingredients contain at least one compound according to theinvention. A dosage unit contains about 0.1-100 mg of activeingredient(s). In humans, the dosage of the compounds according to theinvention is approximately 0.1-1000 mg per day.

The examples below are used for a more detailed explanation of theinvention, without intending that it be limited to these examples:

Production of the Components of General Formula a from Pantolactone orfrom Malonic Acid Dialkyl Esters:

EXAMPLE 1(3S)-1-Oxa-2-oxo-3-(tetrahydropyran-2(RS)-yloxy)-4,4-dimethyl-cyclopentane

The solution of 74.1 g (569 mmol) of D-(−)-pantolactone in 1 1 ofanhydrous dichloromethane is mixed with 102 ml of 3,4-dihydro-2H-pyran,2 g of p-toluenesulfonic acid-pyridinium salt under an atmosphere of dryargon, and it is stirred for 16 hours at 23° C. It is poured into asaturated sodium bicarbonate solution, the organic phase is separatedand dried on sodium sulfate. After filtration and removal of thesolvent, the residue is chromatographed on about 5 kg of fine silica gelwith a mixture of n-hexane and ethyl acetate. 119.6 g (558 mmol, 98%) ofthe title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=1.13 (3H), 1.22 (3H), 1.46-1.91 (6H), 3.50-3.61 (1H),3.86 (1H), 3.92 (1H), 4.01 (1H), 4.16 (1H), 5.16 (1H) ppm.

EXAMPLE 2(2RS,3S)-1-Oxa-2-hydroxy-3-(tetrahydropyran-2(RS)-yloxy)-4,4-dimethyl-cyclopentane

The solution of 117.5 g (548 mmol) of the compound, presented accordingto Example 1, in 2.4 l of anhydrous toluene is cooled under anatmosphere of dry argon to −70° C., mixed within 1 hour with 540 ml of a1.2 molar solution of diisobutylaluminum hydride in toluene, and it isstirred for 3 more hours at −70° C. It is allowed to heat to −20° C.,mixed with saturated ammonium chloride solution, water, and theprecipitated aluminum salts are separated by filtration on Celite. Thefiltrate is washed with water and saturated sodium chloride solution anddried on magnesium sulfate. After filtration and removal of the solvent,111.4 g (515 mmol, 94%) of the title compound is isolated as a colorlessoil, which is further reacted without purification.

IR(CHCl₃): 3480, 3013, 2950, 2874, 1262, 1133, 1074, 1026 and 808 cm⁻¹.

EXAMPLE 3(3S)-2,2-Dimethyl-3-(tetrahydropyran-2(R)-yloxy)-pent-4-en-1-ol and(3S)-2,2-dimethyl-3-(tetrahydropyran-2(S)-yloxy)-pent-4-en-1-ol

The suspension of 295 g of methyl-triphenylphosphonium bromide in 2.5 lof anhydrous tetrahydrofuran is mixed under an atmosphere of dry argonat −60° C. with 313 ml of a 2.4 molar solution of n-butyllithium inn-hexane, allowed to heat to 23° C., stirred for one more hour andcooled to 0° C. It is mixed with the solution of 66.2 g (306 mmol) ofthe compound, presented according to Example 2, in 250 ml oftetrahydrofuran, allowed to heat to 23° C. and stirred for 18 hours. Itis poured into a saturated sodium bicarbonate solution, extractedseveral times with dichloromethane, and the combined organic extractsare dried on sodium sulfate. After filtration and removal of thesolvent, the residue is chromatographed on about 5 l of fine silica gelwith a gradient system that consists of n-hexane and ethyl acetate. 36.5g (170 mmol, 56%) of the nonpolar THP-isomers of the title compound,14.4 g (67.3 mmol, 22%) of the polar THP-isomers of the title compound,as well as 7.2 g (33.3 mmol; 11%) of the starting material are isolatedin each case as a colorless oil.

¹H-NMR (CDCl₃), nonpolar isomer: δ=0.78 (3H), 0.92 (3H), 1.41-1.58 (4H),1.63-1.87 (2H), 3.18 (1H), 3.41 (1H), 3.48 (1H), 3.68 (1H), 3.94 (1H),4.00 (1H), 4.43 (1H), 5.19 (1H), 5.27 (1H), 5.75 (1H) ppm.

¹H-NMR (CDCl₃), polar isomer: δ=0.83 (3H), 0.93 (3H), 1.42-1.87 (6H),2.76 (1H), 3.30 (1H), 3.45 (1H), 3.58 (1H), 3.83 (1H), 3.89 (1H), 4.65(1H), 5.12-5.27 (2H), 5.92 (1H) ppm.

EXAMPLE 4(3S)-1-(tert-Butyldiphenylsilyloxy)-2,2-dimethyl-pentane-3-(tetrahydropyran-2-yloxy)-pent-4-ene

The solution of 59.3 g (277 mmol) of the THP-isomer-mixture, presentedaccording to Example 3, in 1000 ml of anhydrous dimethylformamide ismixed under an atmosphere of dry argon with 28 g of imidazole, 85 ml oftert-butyldiphenylchlorosilane and stirred for 16 hours at 23° C. It ispoured into water, extracted several times with dichloromethane, thecombined organic extracts are washed with water and dried on sodiumsulfate. After filtration and removal of the solvent, the residue ischromatographed on fine silica gel with a gradient system that consistsof n-hexane and ethyl acetate. 106.7 g (236 mmol, 85%) of the titlecompound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.89 (3H), 0.99 (3H), 1.08 (9H), 1.34-1.82 (6H), 3.40(1H), 3.51 (2H), 3.76 (1H), 4.02 (1H), 4.67 (1H), 5.18 (1H), 5.23 (1H),5.68 (1H), 7.30-7.48 (6H), 7.60-7.73 (4H) ppm.

EXAMPLE 5(3S)-1-(tert-Butyldiphenylsilyloxy)-2,2-dimethyl-3-(tetrahydropyran-2-yloxy)-pentan-5-ol

The solution of 3.09 g (6.83 mmol) of the compound, presented accordingto Example 4, in 82 ml of tetrahydrofuran is mixed with 13.1 ml of a 1molar solution of borane in tetrahydrofuran under an atmosphere of dryargon at 23° C., and it is allowed to react for 1 hour. Then, whilebeing cooled with ice, it is mixed with 16.4 ml of a 5% sodium hydroxidesolution as well as 8.2 ml of a 30% hydrogen peroxide solution, and itis stirred for another 30 minutes. It is poured into water, extractedseveral times with ethyl acetate, the combined organic extracts arewashed with water, saturated sodium chloride solution and dried onmagnesium sulfate. The residue that is obtained after filtration andremoval of the solvent is purified by chromatography on fine silica gelwith a gradient system that consists of n-hexane and ethyl acetate. 1.78g (3.78 mmol, 55%) of the title compound is isolated as achromatographically separable mixture of the two THP-epimeres, as wellas 0.44 g (1.14 mmol, 17%) of the title compound of Example 6 in eachcase as a colorless oil.

¹H-NMR (CDCl₃), nonpolar THP-isomer: δ=0.80 (3H), 0.88 (3H), 1.10 (9H),1.18-1.80 (9H), 3.27 (1H), 3.39 (1H), 3.48 (1H), 3.64 (1H), 3.83 (1H),3.90-4.08 (2H), 4.49 (1H), 7.31-7.50 (6H), 7.58-7.73 (4H) ppm.

¹H-NMR (CDCl₃), polar THP-isomer: δ=0.89 (3H), 0.98 (3H), 1.08 (9H),1.36-1.60 (4H), 1.62-1.79 (3H), 1.88 (1H), 2.03 (1H), 3.37 (1H), 3.50(1H), 3.57 (1H), 3.62-3.83 (4H), 4.70 (1H), 7.30-7.48 (6H), 7.61-7.73(4H) ppm.

EXAMPLE 6(3S)-1-(tert-Butyldiphenylsilyloxy)-2,2-dimethyl-pentane-3,5-diol

Analogously to Example 5, the solution of 570 mg (1.55 mmol) of thecompound that is presented according to Example 12 is reacted, and afterworking-up and purification, 410 mg (1.06 mmol, 68%) of the titlecompound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.82 (3H), 0.93 (3H), 1.08 (9H), 1.56-1.79 (2H), 3.11(1H), 3.50 (2H), 3.78-3.92 (3H), 4.02 (1H), 7.34-7.51 (6H), 7.61-7.71(4H) ppm.

EXAMPLE 7 Variant I4(S)-[2-Methyl-1-(tert-butyldiphenylsilyloxy)-prop-2-yl]-2,2-dimethyl-[1,3]dioxane

The solution of 100 mg (0.212 mmol) of the compounds, presentedaccording to Example 5, in 2.6 ml of anhydrous acetone is mixed with78.9 mg of copper(II) sulfate, a spatula tip full of p-toluenesulfonicacid-monohydrate under an atmosphere of dry argon, and it is stirred for16 hours at 23° C. It is mixed with saturated sodium bicarbonatesolution, extracted several times with diethyl ether, washed withsaturated sodium chloride solution and dried on sodium sulfate. Theresidue that is obtained after filtration and removal of the solvent ispurified by chromatography on fine silica gel with a gradient systemthat consists of n-hexane and ethyl acetate. 24 mg (56 μmol, 27%) of thetitle compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.83 (3H), 0.89 (3H), 1.07 (9H), 1.30 (1H), 1.36 (3H),1.44 (3H), 1.71 (1H), 3.24 (1H), 3.62 (1H), 3.86 (1H), 3.91-4.03 (2H),7.31-7.48 (6H), 7.61-7.74 (4H) ppm.

Variant II

Analogously to Example 7, 320 mg (0.88 mmol) of the compound that ispresented according to Example 6 is reacted; variant 1, and afterworking-up and purification, 234 mg (0.548 mmol, 62%) of the titlecompound is isolated.

Variant III

The solution of 5.60 g (14.5 mmol) of the compound, presented accordingto Example 6, in 250 ml of anhydrous dichloromethane, is mixed with 10ml of 2,2-dimethoxypropane, 145 mg of camphor-10-sulfonic acid under anatmosphere of dry argon, and it is stirred for 6 hours at 23° C. It ismixed with triethylamine, diluted with ethyl acetate, washed withsaturated sodium bicarbonate solution and dried on sodium sulfate. Afterfiltration and removal of the solvent, the residue is chromatographed onfine silica gel with a mixture of n-hexane and ethyl acetate. 5.52 g(12.9 mmol, 89%) of the title compound is isolated as a colorless oil.

EXAMPLE 8(4S)-4-(2-Methyl-1-hydroxy-prop-2-yl)-2,2-dimethyl-[1,3]dioxane

The solution of 5.6 g (13.1 mmol) of the compound, presented accordingto Example 7, in 75 ml of anhydrous tetrahydrofuran is mixed with 39 mlof a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuranunder an atmosphere of dry argon, and it is heated for 16 hours to 50°C. It is mixed with saturated sodium bicarbonate solution, extractedseveral times with ethyl acetate, washed with saturated sodium chloridesolution and dried on sodium sulfate. The residue that is obtained afterfiltration and removal of the solvent is purified by chromatography onfine silica gel with a gradient system that consists of n-hexane andethyl acetate. 2.43 g (12.9 mmol, 99%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.87 (3H), 0.90 (3H), 1.35 (1H), 1.37 (3H), 1.43 (3H),1.77 (1H), 2.93 (1H), 3.36 (1H), 3.53 (1H), 3.79 (1H), 3.87 (1H), 3.96(1H) ppm.

EXAMPLE 9 (4S)-4-(2-Methyl-1-oxo-prop-2-yl)-2,2-dimethyl-[1,3]dioxane

The solution of 0.13 ml of oxalyl chloride in 5.7 ml of anhydrousdichloromethane is cooled under an atmosphere of dry argon to −70° C.,mixed with 0.21 ml of dimethyl sulfoxide, the solution of 200 mg (1.06mmol) of the compound, presented according to Example 8, in 5.7 ml ofanhydrous dichloromethane, and it is stirred for 0.5 hour. Then, it ismixed with 0.65 ml of triethylamine, allowed to react for 1 hour at −30°C. and mixed with n-hexane and saturated sodium bicarbonate solution.The organic phase is separated, the aqueous phase is extracted once morewith n-hexane, the combined organic extracts are washed with water anddried on magnesium sulfate. The residue that is obtained afterfiltration and removal of the solvent is further reacted withoutpurification.

EXAMPLE 10(4S)-4-(2-methyl-3(RS)-hydroxy-pent-2-yl)-2,2-dimethyl-[1,3]dioxane

The solution of 900 mg (4.83 mmol) of the compound, presented accordingto Example 9, in 14 ml of anhydrous diethyl ether is mixed with 2.42 mlof a 2.4 molar solution of ethylmagnesium bromide in diethyl ether underan atmosphere of dry argon at 0° C., allowed to heat to 23° C. andstirred for 16 hours. It is mixed with saturated ammonium chloridesolution, the organic phase is separated and dried on sodium sulfate.The residue that is obtained after filtration and removal of the solventis purified by chromatography on fine silica gel with a gradient systemthat consists of n-hexane and ethyl acetate. 321 mg (1.48 mmol, 31%) ofthe nonpolar 3R- or 3S-epimeres of the title compound, 542 mg (2.51mmol, 52%) of the polar 3S- or 3R-epimeres of the title compound and 77mg of the title compound that is described in Example 8 are isolated ineach case as a colorless oil.

¹H-NMR (CDCl₃) nonpolar isomer: δ=0.86 (3H), 0.89 (3H), 1.03 (3H),1.25-1.37 (2H), 1.37 (3H), 1.46 (3H), 1.49 (1H), 1.84 (1H), 3.35 (1H),3.55 (1H), 3.81-4.02 (3H) ppm.

¹H-NMR (CDCl₃) polar isomer: δ=0.72 (3H), 0.91 (3H), 0.99 (3H),1.25-1.44 (2H), 1.38 (3H), 1.43-1.60 (1H), 1.49 (3H), 1.76 (1H), 3.39(1H), 3.63 (1H), 3.79-4.03 (3H) ppm.

EXAMPLE 11 (4S)-4-(2-Methyl-3-oxo-pent-2-yl)-2,2-dimethyl-[1,3]dioxane

The solution of 850 mg (3.93 mmol) of a mixture of the compound,presented according to Example 10, in 63 ml of anhydrous dichloromethaneis mixed with molecular sieve (4A, about 80 spheres), 690 mg ofn-methylmorpholino-N-oxide, and 70 mg of tetrapropylammoniumperruthenate, and it is stirred for 16 hours at 23° C. under anatmosphere of dry argon. It is concentrated by evaporation, and thecrude product that is obtained is purified by chromatography on about200 ml of fine silica gel with a gradient system that consists ofn-hexane and ethyl acetate. 728 mg (3.39 mmol, 86%) of the titlecompound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=1.00 (3H), 1.07 (3H), 1.11 (3H), 1.31 (1H), 1.32 (3H),1.41 (3H), 1.62 (1H), 2.52 (2H), 3.86 (1H), 3.97 (1H), 4.05 (1H) ppm.

EXAMPLE 12(3S)-1-(tert-Butyldiphenylsilyloxy)-2,2-dimethyl-3-hydroxy-pent-4-ene

The solution of 106.7 g (236 mmol) of the compound, presented accordingto Example 4, in 1.5 l of anhydrous ethanol is mixed with 5.9 g ofpyridinium-p-toluenesulfonate under an atmosphere of dry argon, and itis heated for 6 hours to 50° C. After removal of the solvent, theresidue is chromatographed on fine silica gel with a mixture of n-hexaneand ethyl acetate. 82.6 g (224 mmol, 95%) of the title compound isisolated as a colorless oil, in which in addition about 5 g ofethoxy-tetrahydropyran is contained.

¹H-NMR (CDCl₃) of an analytic sample: δ=0.89 (6H), 1.08 (9H), 3.45 (1H),3.49 (1H), 3.58 (1H), 4.09 (1H), 5.21 (1H), 5.33 (1H), 5.93 (1H),7.34-7.51 (6H), 7.63-7.73 (4H) ppm.

EXAMPLE 13(4S)-4-((2RS)-3-Methyl-2-hydroxy-prop-3-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 10, 450 mg (2.42 mmol) of the compound that ispresented according to Example 9 is reacted with use of methylmagnesiumbromide. After working-up and purification, 431 mg (2.13 mmol, 88%) of achromatographically separable mixture of the epimeric title compounds isisolated as a colorless oil.

EXAMPLE 14 (4S)-4-(3-Methyl-2-oxo-prop-3-yl)-2,2-dimethyl-[1,3]dioxane

420 mg (2.08 mmol) of the compound that is presented according toExample 13 is reacted analogously to Example 11. After working-up andpurification, 388 mg (1.94 mmol, 93%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=1.08 (3H), 1.12 (3H), 1.33 (3H), 1.35 (1H), 1.42 (3H),1.63 (1H), 2.17 (3H), 3.87 (1H), 3.98 (1H), 4.04 (1H) ppm.

EXAMPLE 15(4S)-4-((3RS)-2-Methyl-3-hydroxy-hex-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 10, 450 mg (2.42 mmol) of the compound that ispresented according to Example 9 is reacted with use ofn-propylmagnesium bromide. After working-up and purification, a total of244 mg (1.06 mmol, 44%) of a separable mixture of epimeric titlecompounds as well as 191 mg of the title compound that is described inExample 8 are isolated in each case as a colorless oil.

¹H-NMR (CDCl₃) nonpolar isomer: δ=0.87 (3H), 0.89 (3H), 0.94 (3H),1.25-1.52 (4H), 1.38 (3H), 1.45 (3H), 1.66 (1H), 1.85 (1H), 3.46 (1H),3.80-4.02 (4H) ppm.

¹H-NMR (CDCl₃) polar isomer: δ=0.73 (3H), 0.92 (3H), 0.95 (3H),1.19-1.84 (6H), 1.37 (3H), 1.49 (3H), 3.49 (1H), 3.60 (1H), 3.80-4.03(3H) ppm.

EXAMPLE 16 (4S)-4-(2-Methyl-3-oxo-hex-2-yl)-2,2-dimethyl-[1,3]dioxane

230 mg (1.00 mmol) of the compounds presented according to Example 15are reacted analogously to Example 11. After working-up andpurification, 185 mg (0.81 mmol, 81%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.88 (3H), 1.04 (3H), 1.12 (3H), 1.22-1.37 (1H), 1.31(3H), 1.40 (3H), 1.48-1.71 (3H), 2.46 (2H), 3.83 (1H), 3.96 (1H), 4.04(1H) ppm.

EXAMPLE 17 (4R)-4-(2-Methyl-3-oxo-pent-2-yl)-2,2-dimethyl-[1,3]-dioxane

Starting from L-(+)-pantolactone, the title compound is producedanalogously to the processes that are described in Examples 1 to 9 and12 via the respective enantiomer intermediate stages.

¹H-NMR (CDCl₃): δ=1.00 (3H), 1.07 (3H), 1.12 (3H), 1.24-1.37 (1H), 1.31(3H), 1.40 (3H), 1.61 (1H), 2.50 (2H), 3.84 (1H), 3.95 (1H), 4.03 (1H)ppm.

EXAMPLE 18 (4R)-4-(3-Methyl-2-oxo-prop-3-yl)-2,2-dimethyl-[1,3]dioxane

Starting from L-(+)-pantolactone, the title compound is producedanalogously to the processes that are described in Examples 1 to 9 and12 to 14 via the respective enantiomer intermediate stages.

¹H-NMR (CDCl₃): δ=1.07 (3H), 1.12 (3H), 1.30-1.39 (1H), 1.33 (3H), 1.43(3H), 1.62 (1H), 2.17 (3H), 3.86 (1H), 3.96 (1H), 4.03 (1H) ppm.

EXAMPLE 19 (4R)-4-(2-Methyl-3-oxo-hex-2-yl)-2,2-dimethyl-[1,3]dioxane

Starting from L-(+)-pantolactone, the title compound is producedanalogously to the processes that are described in Examples 1 to 9, 12,15 and 16 via the respective enantiomer intermediate stages.

¹H-NMR (CDCl₃): δ=0.88 (3H), 1.04 (3H), 1.12 (3H), 1.22-1.37 (1H), 1.31(3H), 1.41 (3H), 1.48-1.72 (3H), 2.47 (2H), 3.84 (1H), 3.96 (1H), 4.05(1H) ppm.

EXAMPLE 20(2S,4S)-2-(2-Cyanophenyl)-4-[2-methyl-1-(tert-butyldiphenylsilyloxy)-prop-2-yl]-[1,3]dioxane

The solution of 1.00 g (2.59 mmol) of the compound, presented accordingto Example 6, in 50 ml of benzene is mixed with 850 mg of2-cyanobenzaldehyde, a spatula tip full of p-toluenesulfonicacid-monohydrate, and it is refluxed for 16 hours in a water separatorunder an atmosphere of dry argon. It is mixed with 0.5 ml oftriethylamine, diluted with ethyl acetate, washed with saturated sodiumbicarbonate solution and dried on sodium sulfate. After filtration andremoval of the solvent, the residue is chromatographed on fine silicagel with a mixture of n-hexane and ethyl acetate. 1.22 g (2.44 mmol,94%) of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.99 (6H), 1.05 (9H), 1.47 (1H), 1.98 (1H), 3.34 (1H),3.63 (1H), 3.96-4.09 (2H), 4.31 (1H), 5.75 (1H), 7.17 (2H), 7.24-7.51(5H), 7.51-7.74 (7H) ppm.

EXAMPLE 21(2S,4S)-2-(2-Cyanophenyl)-4-(2-methyl-1-hydroxy-prop-2-yl)-[1,3]dioxane

Analogously to Example 8, 1.22 g (2.44 mmol) of the compound that ispresented according to Example 20 is reacted, and after working-up andpurification, 593 mg (2.27 mmol, 93%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.89 (3H), 0.97 (3H), 1.51 (1H), 2.01 (1H), 2.42 (1H),3.31 (1H), 3.72 (1H), 3.97 (1H), 4.02 (1H), 4.39 (1H), 5.78 (1H), 7.46(1H), 7.63 (1H), 7.69 (1H), 7.75 (1H) ppm.

EXAMPLE 22(2S,4S)-2-(2-Cyanophenyl)-4-(2-methyl-1-oxo-prop-2-yl)-[1,3]-dioxane

Analogously to Example 9, 570 mg (2.18 mmol) of the compound that ispresented according to Example 21 is reacted, and after working-up, 780mg of the title compound is isolated as a yellow oil, which is furtherreacted without purification.

EXAMPLE 23(2S,4S)-2-(2-Cyanophenyl)-4-((3RS)-2-methyl-3-hydroxy-pent-2-yl)-[1,3]-dioxane

Analogously to Example 10, 780 mg (max. 2.18 mmol) of the crude productthat is presented according to Example 22 is reacted, and afterworking-up and purification, 468 mg (1.62 mmol, 74%) of the epimerictitle compounds is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.81-1.09 (9H), 1.22-1.43 (1H), 1.43-1.70 (2H), 2.04(1H), 2.35 (0.55H), 2.89 (0.45H), 3.41-3.59 (1H), 3.89-4.13 (2H), 4.36(1H), 5.78 (0.45H), 5.81 (0.55H), 7.45 (1H), 7.54-7.78 (3H) ppm.

EXAMPLE 24(2S,4S)-2-(2-Cyanophenyl)-4-(2-methyl-3-oxo-pent-2-yl)-[1,3]dioxane

Analogously to Example 11, 463 mg (1.60 mmol) of the compound that ispresented according to Example 23 is reacted, and after working-up andpurification, 420 mg (1.46 mmol, 91%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=1.00 (3H), 1.19 (3H), 1.24 (3H), 1.49 (1H), 1.92 (1H),2.56 (2H), 4.3 (1H), 4.16 (1H), 4.32 (1H), 5.78 (1H), 7.44 (1H), 7.60(1H), 7.64-7.72 (2H) ppm.

EXAMPLE 25(4S,2S)-4-[2-Methyl-1-(tert-butyldiphenylsilyloxy)-prop-2-yl]-2-phenyl-[1,3]dioxane

Analogously to Example 20, 1.00 g (2.59 mmol) of the compound, presentedaccording to Example 6, in 50 ml of toluene is reacted with use ofbenzaldehyde, and after working-up and purification, 1.2 g (2.53 mmol,98%) of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.93 (3H), 1.00 (3H), 1.07 (9H), 1.43 (1H), 1.92 (1H),3.30 (1H), 3.72 (1H), 3.95 (1H), 4.00 (1H), 4.30 (1H), 5.53 (1H), 7.18(2H), 7.29-7.49 (9H), 7.61 (2H), 7.67 (2H) ppm.

EXAMPLE 26(4S,2S)-4-(2-Methyl-1-hydroxy-prop-2-yl)-2-phenyl-[1,3]dioxane

Analogously to Example 8, 1.20 g (2.53 mmol) of the compound that ispresented according to Example 25 is reacted, and after working-up andpurification, 518 mg (2.19 mmol, 87%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃) δ=0.98 (6H), 1.49 (1H), 2.00 (1H), 2.49 (1H), 3.46 (1H),3.62 (1H), 3.81 (1H), 3.98 (1H), 4.33 (1H), 5.51 (1H), 7.30-7.41 (3H),7.41-7.51 (2H) ppm.

EXAMPLE 27 (2S,4S)-4-(2-Methyl-1-oxo-prop-2-yl)-2-phenyl-[1,3]dioxane

Analogously to Example 9, 500 mg (2.12 mmol) of the compound that ispresented according to Example 26 is reacted, and after working-up, 715mg of the title compound is isolated as a yellow oil, which is furtherreacted without purification.

EXAMPLE 28(2S,4S)-4-((3RS)-2-Methyl-3-hydroxy-pent-2-yl)-2-phenyl-[1,3]dioxane

Analogously to Example 10, 715 mg (max. 2.12 mmol) of the crude productthat is presented according to Example 27 is reacted, and afterworking-up and purification, 440 mg (1.66 mmol, 79%) of the epimerictitle compounds is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.80-1.10 (9H), 1.23-1.42 (1H), 1.42-1.70 (2H),1.90-2.16 (1H), 2.92 (0.6H), 3.07 (0.4H), 3.40-3.53 (1H), 3.86 (1H),3.98 (1H), 4.32 (1H), 5.49 (0.4H), 5.55 (0.6H), 7.28-7.40 (3H),7.40-7.51 (2H) ppm.

EXAMPLE 29 (2S,4S)-4-(2-Methyl-3-oxo-pent-2-yl)-2-phenyl-[1,3]dioxane

Analogously to Example 11, 435 mg 91.65 mol) of the compound that ispresented according to Example 28 is reacted, and after working-up andpurification, 410 mg (1.56 mmol, 95%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=1.02 (3H), 1.17 (3H), 1.23 (3H), 1.44 (1H), 1.84 (1H),2.58 (2H), 3.97 (1H), 4.06 (1H), 4.30 (1H), 5.50 (1H), 7.28-7.49 (5H)ppm.

EXAMPLE 30(4S)-4-[2-Methyl-1-(tert-butyldiphenylsilyloxy)-prop-2-yl]-2,2-pentamethylene-[1,3]dioxane

Analogously to Example 20, 1.00 g (2.59 mmol) of the compound, presentedaccording to Example 6, in 50 mol of toluene is reacted with use ofcyclohexanone, and after working-up and purification, 1.09 g (2.34 mmol,90%) of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.84 (3H), 0.89 (3H), 0.97-1.10 (10H), 1.20-1.64 (9H),1.71 (1H), 2.13 (1H), 3.33 (1H), 3.56 (1H), 3.81 (1H), 3.89 (1H), 3.99(1H), 7.32-7.49 (6H), 7.60-7.74 (4H) ppm.

EXAMPLE 31(4S)-4-(2-Methyl-1-hydroxy-prop-2-yl)-2,2-pentamethylene-[1,3]dioxane

Analogously to Example 8, 1.09 g (2.34 mmol) of the compound that ispresented according to Example 30 is reacted, and after working-up andpurification, 470 mg (2.06 mmol, 88%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.88 (3H), 0.94 (3H), 1.24-1.71 (10H), 1.81 (1H), 2.18(1H), 3.09 (1H), 3.39 (1H), 3.60 (1H), 3.80 (1H), 3.87 (1H), 4.02 (1H)ppm.

EXAMPLE 32(4S)-4-(2-Methyl-1-oxo-prop-2-yl)-2,2-pentamethylene-[1,3]dioxane

Analogously to Example 9, 450 mg (1.97 mmol) of the compound that ispresented according to Example 31 is reacted, and after working-up, 678mg of the title compound is isolated as a yellow oil, which is furtherreacted without purification.

EXAMPLE 33(4S)-4-(2-Methyl-3-hydroxy-pent-2-yl)-2,2-pentamethylene-[1,3]dioxane

Analogously to Example 10, 678 mg (max. 1.97 mmol) of the crude productthat is presented according to Example 32 is reacted, and afterworking-up and purification, 391 mg (1.54 mmol, 77%) of the epimerictitle compounds is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.70-1.08 (9H), 1.23-1.98 (13H), 2.01-2.13 (1H),3.37-3.50 (1H), 3.61 (0.5H), 3.80-4.06 (3.5H) ppm.

EXAMPLE 34(4S)-(2-Methyl-3-oxo-pent-2-yl)-2,2-pentamethylene-[1,3]dioxane

Analogously to Example 11, 386 mg (1.51 mmol) of the compound that ispresented according to Example 33 is reacted, and after working-up andpurification, 376 mg (1.48 mmol, 98%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=1.01 (3H), 1.09 (3H), 1.17 (3H), 1.22-1.38 (3H),1.40-1.72 (8H), 2.15 (1H), 2.57 (2H), 3.81 (1H), 3.92-4.07 (2H) ppm.

EXAMPLE 35(4S)-4-[2-Methyl-1-(tert-butyldiphenylsilyloxy)-prop-2-yl]-2,2-tetramethylene-[1,3]dioxane

Analogously to Example 20, 1.00 g (2.59 mmol) of the compound, presentedaccording to Example 6, in 50 ml of toluene is reacted with use ofcyclopentanone, and after working-up and purification, 997 mg (2.20mmol, 85%) of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.84 (3H), 0.88 (3H), 0.99-1.10 (10H), 1.30 (1H),1.50-1.99 (8H), 3.23 (1H), 3.60 (1H), 3.80-3.98 (3H), 7.31-7.49 (6H),7.61-7.73 (4H) ppm.

EXAMPLE 36(4S)-4-(2-Methyl-1-hydroxy-prop-2-yl)-2,2-tetramethylene-[1,3]dioxane

Analogously to Example 8, 997 mg (2.20 mmol) of the compound that ispresented according to Example 35 is reacted, and after working-up andpurification, 415 mg (1.94 mmol, 88%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃):δ=0.90 (6H), 1.36 (1H), 1.53-2.02 (9H), 2.93 (1H), 3.39(1H), 3.55 (1H), 3.70 (1H), 3.87 (1H), 3.96 (1H) ppm.

EXAMPLE 37(4S)-4-(2-Methyl-1-oxo-prop-2-yl)-2,2-tetramethylene-[1,3]dioxane

Analogously to Example 9, 400 mg (1.87 mmol) of the compound that ispresented according to Example 36 is reacted, and after working-up, 611mg of the title compound is isolated as a yellow oil, which is furtherreacted without purification.

EXAMPLE 38(4S)-4-(2-Methyl-3-hydroxy-pent-2-yl)-2,2-tetramethylene-[1,3]dioxane

Analogously to Example 10, 611 mg (max. 1.87 mmol) of the compound thatis presented according to Example 37 is reacted, and after working-upand purification, 353 mg (1.46 mol, 78%) of the epimeric title compoundsis isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.71-1.09 (9H), 1.20-1.44 (2H), 1.44-1.78 (5H),1.78-2.02 (5H), 3.32-3.44 (1H), 3.51-3.60 (1H), 3.76 (1H), 3.80-4.02(2H) ppm.

EXAMPLE 39(4S)-4-(2-Methyl-3-oxo-pent-2-yl)-2,2-tetramethylene-[1,3]dioxane

Analogously to Example 11, 348 mg (1.44 mmol) of the compound that ispresented according to Example 38 is reacted, and after working-up andpurification, 332 mg (1.38 mmol, 96%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=1.00 (3H), 1.07 (3H), 1.17 (3H), 1.31 (1H), 1.50-2.00(9H), 2.52 (2H), 3.84 (1H), 3.88-3.99 (2H) ppm.

EXAMPLE 40 1,1-Cyclobutanedimethanol

170 ml of a 1.2 molar solution of diisobutylaluminium hydride is addedin drops to a solution of 20 g (99.9 mmol) of1,1-cyclobutanedicarboxylic acid diethyl ester in 200 ml of absolutetetrahydrofuran at 0° C. It is allowed to stir for one more hour at 0°C., and then 30 ml of water is added. It is filtered on Celite. Thefiltrate is dried with sodium sulfate and concentrated by evaporation ina vacuum. The crude product that is obtained (9.9 g, 85.2 mmol, 85%) isused without purification in the next step.

EXAMPLE 411-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-methyl]cyclobutanemethanol

A solution of 9.9 g (85 mmol) of the compound, presented according toExample 40, in 100 ml of absolute tetrahydrofuran is added to asuspension of 3.4 g of sodium hydride (60% in oil) in 35 ml of absolutetetrahydrofuran at 0° C. It is allowed to stir for 30 more minutes, andthen a solution of 12.8 g of tert-butyldimethylsilyl chloride in 50 mlof tetrahydrofuran is added. It is allowed to stir for one more hour at25° C., and then the reaction mixture is poured onto saturated aqueoussodium bicarbonate solution. It is extracted with ethyl acetate. Theorganic phase is washed with saturated sodium chloride solution anddried on sodium sulfate. After the solvent is drawn off in a vacuum, thecrude product that is obtained is purified by column chromatography onsilica gel with a mixture of hexane/ethyl acetate. 13.5 g (58.6 mmol,69%) of the title compound is obtained.

¹H-NMR (CDCl₃): δ=0.04 (6H), 0.90 (9H), 1.70-2.00 (6H), 3.70 (4H) ppm.

EXAMPLE 421-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-methyl]cyclobutanecarbaldehyde

8 ml of oxalyl chloride is dissolved in 100 ml of dichloromethane. It iscooled to −78° C., and 13 ml of dimethyl sulfoxide is added. It isallowed to stir for 3 more minutes, and then a solution of 13.5 g (58.6mmol) of the compound, presented according to Example 41, in 80 ml ofdichloromethane is added. After another 15 minutes of stirring time, 58ml of triethylamine is added in drops. Then, it is allowed to heat to 0°C. Then, the reaction mixture is poured onto saturated sodiumbicarbonate solution. It is extracted with dichloromethane, the organicphase is washed with saturated sodium chloride solution, dried on sodiumsulfate and concentrated by evaporation in a vacuum. Afterchromatography of the crude product on silica gel with a mixture ofhexane/ethyl acetate, 7.7 g (33.7 mmol, 58%) of the title compound isobtained.

¹H-NMR (CDCl₃): δ=9.70 s (1H), 3.83 s (2H), 2.20-2.30 m (2H), 1.85-2.00m (4H), 0.90 s (9H), 0.03 s (6H) ppm.

EXAMPLE 43 [1R-[1α(R*)2β]]-2-Phenylcyclohexyl3-[1-[[[dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutyl]-3-hydroxypropanoate(A) and [1R-[1α(S*)2β]]-2-phenylcyclohexyl3-[1-[[[dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutyl]-3-hydroxypropanoate(B)

Lithium diisopropylamide is produced in absolute tetrahydrofuran from7.2 ml of diisopropylamine and butyllithium (32 ml of a 1.6 molarsolution in hexane). Then, a solution of 11.2 g(1R-trans)-2-phenylcyclohexyl acetate in 100 ml of absolutetetrahydrofuran is added at −78° C., and it is allowed to stir for 30more minutes at this temperature. Then, a solution of 7.7 g (33.7 mmol)of the compound, presented according to Example 42, in 50 ml oftetrahydrofuran is added. It is allowed to stir for 1.5 more hours at−78° C., and then the reaction mixture is poured onto saturated aqueousammonium chloride solution. It is extracted with ethyl acetate, theorganic phase is washed with saturated sodium chloride solution, driedon sodium sulfate and concentrated by evaporation in a vacuum. Aftercolumn chromatography of the crude product on silica gel with a mixtureof hexane/ethyl acetate, 6.34 g (14.2 mmol, 42%) of title compound A and4.22 g (9.4 mmol, 28%) of title compound B are obtained.

¹H-NMR (CDCl₃) of A: δ=0.04 (6H), 0.98 (9H), 2.69 (1H), 3.08 (1H), 3.60(1H), 3.67 (1H), 3.78-3.84 (1H), 4.97 (1H), 7.15-7.30 (5H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.03 (6H), 0.90 (9H), 2.68 (1H), 2.80 (1H), 3.56(2H), 3.68-3.72 (1H), 4.99 (1H), 7.18-7.30 m (5H) ppm.

EXAMPLE 44(S)-1-[1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutyl]-1,3-propanediol

4 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene isadded in drops to a solution of 1 g (2.24 mmol) of compound A, presentedaccording to Example 43, in 10 ml of absolute toluene at 0° C. It isallowed to stir for 1.5 more hours at 0° C., and then 5 ml of water isadded. It is filtered on Celite. The filtrate is dried on sodium sulfateand concentrated by evaporation in a vacuum. After column chromatographyof the crude product on silica gel with a mixture of hexane/ethylacetate, 370 mg (1.35 mmol, 60%) of the title compound is obtained.

¹H-NMR (CDCl₃): δ=0.05 (6H), 0.90 (9H), 1.55-1.60 (2H), 1.80 (2H), 1.90(3H), 2.10 (1H), 3.75 (1H), 3.85-3.95 (4H) ppm.

EXAMPLE 45(S)-2,2-Dimethyl-4-[1-[[[dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutyl]-1,3-dioxane

370 mg (1.35 mmol) of the compound that is presented according toExample 44 is dissolved in 10 ml of acetone. A spatula tip full ofp-toluenesulfonic acid is added, and it is allowed to stir for 2 morehours at 25° C. Then, the reaction mixture is poured onto saturatedsodium bicarbonate solution. It is extracted with ethyl acetate, theorganic phase is washed with saturated sodium chloride solution, driedon sodium sulfate and concentrated by evaporation in a vacuum. Aftercolumn chromatography on silica gel with a mixture of hexane/ethylacetate, 338 mg (1.07 mmol, 79%) of the title compound is obtained.

¹H-NMR (CDCl₃): δ=0.03 (6H), 0.88 (9H), 1.38 (3H), 1.42 (3H), 1.50-1.80(4H), 2.00 (1H), 3.52 (1H), 3.62 (1H), 3.85-4.00 (3H) ppm.

EXAMPLE 46(R)-1-[1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]-cyclobutyl]-1,3-propanediol

Analogously to Example 44, 700 mg (1.57 mmol) of compound B that ispresented according to Example 43 is reacted, and after working-up andpurification, 250 mg (0.91 mmol, 58%) of the title compound is isolated.

The coverage of the ¹H-NMR spectrum is identical to that described inExample 44.

EXAMPLE 47(R)-2,2-Dimethyl-4-[1-[[[dimethyl(1,1-dimethylethyl)silyl[oxy]methyl]cyclobutyl]-1,3-dioxane

Analogously to Example 45, 250 mg (0.91 mmol) of the compound that ispresented according to Example 46 is reacted, and after working-up andpurification, 228 mg (0.72 mmol, 60%) of the title compound is isolated.

The coverage of the ¹H-NMR spectrum is identical to that described inExample 45.

EXAMPLE 481-[1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutyl]-1,3-propanediol

Analogously to Example 44, 500 g (1.12 mmol) of a mixture of compounds Aand B that are produced according to Example 43 is reacted, and afterworking-up and purification, 190 mg (0.69 mmol, 62%) of the titlecompound is isolated.

The coverage of the ¹H-NMR spectrum is identical to that described inExample 44.

EXAMPLE 492,2-Dimethyl-4-[1-[[[dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutyl]-1,3-dioxane

Analogously to Example 45, 190 mg (0.69 mmol) of the compound that isproduced according to Example 48 is reacted, and after working-up andpurification, 171 mg (0.54 mmol, 79%) of the title compound is isolated.

The coverage of the ¹H-NMR spectrum is identical to that described inExample 45.

EXAMPLE 50 [1R-[1α(3S*),2β]]-2-Phenylcyclohexyl3-[1-[[[dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutyl]-3-[(tetrahydro-2H-pyran-2-yl)oxy]propanoate

Analogously to Example 1, 460 mg (1.03 mmol) of the compound that ispresented according to Example 43 is reacted, and after working-up andpurification, 398 mg (0.75 mmol, 73%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.01 (6H), 0.89 (9H), 1.24-1.97 (19H), 2.15-2.27 (3H),2.66 (1H), 3.12 (1H), 3.50 (2H), 3.58 (1H), 3.98 (1H), 4.52 (1H), 4.87(1H), 7.09-7.27 (5H) ppm.

EXAMPLE 51(S)-3-[1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutyl]-3-[(tetrahydro-2H-pyran-2-yl)oxy]propanoicacid

420 mg (3.75 mmol) of potassium tert-butylate is suspended in 5 ml ofdiethyl ether. 16 μl of water is added, and it is allowed to stir for 5more minutes. Then, a solution of 398 mg (0.75 mmol) of the compound,presented according to Example 50, in 5 ml of diethyl ether is added. Itis allowed to stir for 3 more hours. Then, the reaction solution isdiluted with water and neutralized with 10% hydrochloric acid. It isextracted with dichloromethane, the organic phase is washed withsaturated aqueous sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum. Column chromatography of thecrude product on silica gel with a mixture of hexane/ethyl acetateyields 112 mg (0.3 mmol).

¹H-NMR (CDCl₃): δ=0.01 (6H), 0.90 (9H), 1.30-2.25 (10H), 3.12 (1H), 3.50(2H), 3.58 (1H), 3.98 (1H), 4.45 (1H) ppm.

After the silyl protective group is cleaved by oxidation, the reactionproduct can be converted into aldehyde analogously to Example 9, broughtto reaction with an organometallic compound such as, e.g.,XMgCHR^(5a)R^(5b), for example with ethylmagnesium bromide, analogouslyto Example 10, and converted by subsequent oxidation of the alcoholmixture that is obtained to compounds according to claim 1 analogouslyto Example 11.

If the starting material 1,1-cyclobutanedicarboxylic acid diethyl esteris replaced in Example 40 by other 2-substituted or 2,2-disubstitutedmalonic ester derivatives, for example the following compounds can beproduced analogously to Examples 9, 10 and 40-51:

R^(4a) R^(4b) R^(5a) R^(5b) —(CH₂)₂— H CH₃ —(CH₂)₂— H CH₂—CH₃ —(CH₂)₂— H(CH₂)₂—CH₃ —(CH₂)₂— H CH₂—C₆H₅ —(CH₂)₂— H (CH₂)₂— C₆H₅ —(CH₂)₂— CH₃ CH₃—(CH₂)₂— CH₃ CH₂—C_(3H) —(CH₂)₃— H CH₃ —(CH₂)₃— H CH₂—CH₃ —(CH₂)₃— H(CH₂)₂—CH₃ —(CH₂)₃— H CH₂—C₆H₅ —(CH₂)₃— H (CH₂)₂— C₆H₅ —(CH₂)₃— CH₃ CH₃—(CH₂)₃— CH₃ CH₂—CH₃ —(CH₂)₄— H CH₃ —(CH₂)₄— H CH₂—CH₃ —(CH₂)₄— H(CH₂)₂—CH₃ —(CH₂)₄— H CH₂—C₆H₅ —(CH₂)₄— H (CH₂)₂— C₆H₅ —(CH₂)₄— CH₃ CH₃—(CH₂)₄— CH₃ CH₂—CH₃ CH₃ CH₃ H CH₃ CH₃ CH₃ CH₂— CH₂—CH₃ CH₃ CH₃ CH₃ H(CH₂)₂—CH₃ CH₃ CH₃ H CH₂—C₆H₅ CH₃ CH₃ H (CH₂)₂— C₆H₅ CH₂—CH₃ CH₂— H CH₃CH₃ CH₂—CH₃ CH₂— H CH₂—CH₃ CH₃ CH₂—CH₃ CH₂— H (CH₂)₂—CH₃ CH₃ CH₂—CH₃CH₂— H CH₂—C₆H₅ CH₃ CH₂—CH₃ CH₂— H (CH₂)₂— CH₃ C₆H₅ CH₃ CH₂— H CH₃ CH₃CH₃ CH₂— H CH₂—CH₃ CH₃ CH₃ CH₂— H (CH₂)₂—CH₃ CH₃ CH₃ CH₂— H CH₂—C₆H₅ CH₃CH₃ CH₂— H (CH₂)₂— CH₃ C₆H₅

EXAMPLE 52(3S)-4,4-Dimethyl-5-oxo-3-(tetrahydropyran-2-yloxy)-pent-1-ene

Analogously to Example 9, 5.0 g (23.3 mmol) of the compound that ispresented according to Example 3 is reacted, and after working-up, 6.1 gof the title compound is isolated as a colorless oil, which is furtherreacted without purification.

EXAMPLE 53(3S,5RS)-4,4-Dimethyl-5-hydroxy-3-(tetrahydropyran-2-yloxy)-hept-1-ene

Analogously to Example 10, 6.1 g (max. 23.3 mmol) of the crude productthat is presented according to Example 52 is reacted, and afterworking-up and purification, 1.59 g (6.56 mmol, 28%) of the nonpolardiastereomer and 1.67 g (6.89 mmol, 30%) of the polar diastereomer areisolated in each case as a colorless oil.

¹H-NMR (CDCl₃) nonpolar isomer: δ=0.79 (3H), 0.84 (3H), 1.03 (3H),1.23-1.62 (6H), 1.62-1.88 (2H), 3.41-3.58 (2H), 3.88-4.01 (2H), 4.08(1H), 4.47 (1H), 5.20 (1H), 5.29 (1H), 5.78 (1H) ppm.

¹H-NMR (CDCl₃) polar isomer: δ=0.78 (3H), 0.93 (3H), 1.01 (3H), 1.38(1H), 1.47-1.85 (7H), 3.39-3.57 (3H), 3.90 (1H), 4.04 (1H), 4.62 (1H),5.21 (1H), 5.32 (1H), 5.69 (1H) ppm.

EXAMPLE 54(3S,5S)-4,4-Dimethyl-3-(tetrahydropyran-2-yloxy)-heptane-1,5-diol and/or(3S,5S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-heptane-1,5-diol

Analogously to Example 5, 1.59 g (6.56 mmol) of the nonpolar alcoholthat is presented according to Example 53 is reacted, and afterworking-up, 1.14 g (4.38 mmol, 67%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=0.78 (6H), 1.01 (3H), 1.28 (1H), 1.36-1.64 (6H),1.64-1.93 (4H), 3.41-3.55 (2H), 3.61-3.82 (2H), 387 (1H), 3.99 (1H),4.28 (1H), 4.56 (1H) ppm.

EXAMPLE 55 (3S,5R or5S)-1-Benzoyloxy-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-heptan-5-ol

The solution of 1.04 g (3.99 mmol) of the compound, presented accordingto Example 54, in 20 ml of anhydrous pyridine is mixed under anatmosphere of dry argon with 476 μl of benzoyl chloride, and it isstirred for 16 hours at 23° C. It is poured into a saturated sodiumbicarbonate solution, extracted with dichloromethane and dried on sodiumsulfate. The residue that is obtained after filtration and removal ofthe solvent is purified by chromatography on about 300 ml of fine silicagel with a gradient system that consists of n-hexane and ethyl acetate.785 mg (2.15 mmol, 54%) of the title compound is isolated as a colorlessoil as well as 352 mg of starting material.

¹H-NMR (CDCl₃): δ=0.83 (6H), 1.04 (3H), 1.31 (1H), 1.38-1.58 (5H),1.74-1.99 (3H), 2.12 (1H), 3.40 (1H), 3.52 (1H), 3.90-4.03 (2H),4.28-4.56 (4H), 7.45 (2H), 7.58 (1H), 8.05 (2H) ppm.

EXAMPLE 56(3S)-1-Benzoyloxy-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-heptan-5-one.

Analogously to Example 11, 780 mg (2.14 mmol) of the compound that ispresented according to Example 55 is reacted, and after working-up andpurification, 641 mg (1.77 mmol, 83%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=1.02 (3H), 1.11 (3H), 1.23 (3H), 1.40-1.56 (4H),1.65-1.87 (3H), 1.93 (1H), 2.59 (2H), 3.36 (1H), 3.80 (1H), 4.13 (1H),4.32 (1H), 4.45 (1H), 4.53 (1H), 7.45 (2H), 7.58 (1H), 8.05 (2H) ppm.

EXAMPLE 57(3S)-1-Hydroxy-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-heptan-5-one

The solution of 636 mg (1.75 mmol) of the compound, presented accordingto Example 56, in 25 ml of methanol is mixed with 738 mg of potassiumcarbonate and stirred for 2 hours at 23° C. It is mixed withdichloromethane, filtered off, washed with water, and the organic phaseis dried on sodium sulfate. The residue that is obtained afterfiltration and removal of the solvent is purified by chromatography onabout 100 ml of fine silica gel with a gradient system that consists ofn-hexane and ethyl acetate. 311 mg (1.20 mmol, 69%) of the titlecompound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.98 (3H), 1.07 (3H), 1.18 (3H), 1.44-1.90 (10H), 2.00(1H), 3.50-3.68 (2H), 3.74 (1H), 3.83-4.06 (2H), 4.79 (1H) ppm.

Production of the Components of General Formula A″ with the2-Oxazolidinone Auxiliary Group

Starting Products

A) 2.2-Dimethyl-3-oxopentanal

Aa) 4-(2-Methylprop-1-enyl)morpholine

43.6 g of morpholine is placed in a 250 ml round-bottom three-neckflask. While being cooled in an ice bath, 46 ml of isobutylaldehyde isadded in drops at a temperature of 5° C. over a period of 20 minutes. Inthis case, a sharp rise in temperature was noted (a strongly exothermicreaction). Once the addition process had been completed, the feedstockis refluxed via a water separator for a period of four hours. The volumeof the water separator is filled with isobutylaldehyde. 7.5 ml of H₂O isseparated. Once the reaction has taken place, the reaction mixture isdistilled in a vacuum.

-   -   Oil bath temperature: 85°-90° C.    -   Main fraction m=58.37 g 82.03%    -   Boiling point: 59° C. at 11 mbar    -   Yield: 58.37 g 82.03% Aa).        A) 2,2-Dimethyl-3-oxopentanal

The solution of 77.14 g of propionic acid chloride in 200 ml of etherp.a. is placed in a 1000 ml round-bottom three-neck flask. While beingcooled in an ice bath, a solution of 117.73 g of the compound obtainedunder Aa) in 200 ml of ether p.A. is added in drops within 30 minutes ata reaction temperature of 6° C. Precipitation, a white precipitateappears. Once the addition process is completed, the feedstock is boiledfor 5 hours under reflux and then stirred overnight at room temperature.The white precipitate that is produced, which is sensitive to moisture,is suctioned off, washed with ether, and dried in the oil pump.

-   -   Crude product: m=65.26 g of hydrochloride    -   Post-precipitation can be observed in the filtrate.    -   Crude product m=35.49 g, total: m=100.75 g.

The 100.75 g of hydrochloride is dissolved in 150 ml of H₂O. Then, theaqueous phase is adjusted to pH 0 5 overall with NaHCO₃ and thenextracted four times with 150 ml of ether in each case. The organicphase is washed once with brine and then dried on Na₂SO₄. The ether isdistilled off at normal pressure, and the residue is distilled in avacuum on a small Vigreux column (6 plates).

-   -   Main fraction: m=29.65 g 27.75%    -   Boiling point: 62° C. at 15 mbar    -   Yield: 29.65 g 27.75% A)        B) 2,2-Dimethyl-3-oxo-butanal    -   Execution analogous to A).    -   Feedstock: 58.37 g=413.36 mmol of Aa), M=141.21 g/mol 100 ml of        diethyl ether p.A.    -   32.45 g=413.38 mmol of acetyl chloride, M=0 78.5 g/mol=1.104        g/ml

100 ml of diethyl ether p.A. is stirred over the weekend at roomtemperature.

-   -   Crude product m=72.07 g of hydrochloride    -   For working-up see Ab)    -   Oil bath temperature: 75° C. to 80° C.    -   Main fraction: m=18.75 g 39.74%    -   Boiling point: 50° C. at 11 mbar    -   Yield m=18.7 g 39.6% B)        C) 1-(1-Oxopropyl)cyclobutanecarbaldehyde        Ca) 1,1-Cyclobutanedimethanol

170 ml of a 1.2 molar solution of diisobutylaluminum hydride is added indrops to a solution of 20 g (100 mmol) of 1,1-cyclobutanedicarboxylicacid diethyl ester in 200 ml of absolute tetrahydrofuran at 0° C. It isallowed to stir for one more hour at 0° C., and then 30 ml of water isadded. It is filtered on Celite. The filtrate is dried with sodiumsulfate and concentrated by evaporation in a vacuum. The crude productthat is obtained (9.9 g) is used without purification in the next step.

Cb) 1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutanemethanol

A solution of 9.9 g of Ca) (85 mmol) in 100 ml of absolutetetrahydrofuran is added to a suspension of 3.4 g of sodium hydride (60%in oil, 85 mmol)) in 35 ml of absolute tetrahydrofuran at 0° C. It isallowed to stir for 30 more minutes, and then a solution of 12.8 g oftert-butyldimethylsilyl chloride (85 mmol) in 50 ml of tetrahydrofuranis added. It is allowed to stir for one more hour at 25° C., and thenthe reaction mixture is poured onto saturated aqueous sodium bicarbonatesolution. It is extracted with ethyl acetate. The organic phase iswashed with saturated sodium chloride solution and dried on sodiumsulfate. After the solvent is drawn off in a vacuum, the crude productthat is obtained is purified by column chromatography on silica gel witha mixture of hexane/ethyl acetate. 13.5 g (69%) of the title compound isobtained.

¹H-NMR (CDCl₃): δ=0.04 (6H), 0.90 (9H), 1.70-2.00 (6H), 3.70 (4H) ppm.

Cc)1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutanecarbaldehyde

8 ml of oxalyl chloride is dissolved in 100 ml of dichloromethane. It iscooled to −78° C., and 13 ml of dimethyl sulfoxide is added. It isallowed to stir for 3 more minutes, and then a solution of 13.5 g of Cb)(58.6 mmol) in 80 ml of dichloromethane is added. After 15 more minutesof stirring time, 58 ml of triethylamine is added in drops. Then, it isallowed to heat to 0° C. Then, the reaction mixture is poured ontosaturated sodium bicarbonate solution. It is extracted withdichloromethane, the organic phase is washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. After chromatography of the crude product onsilica gel with a mixture of hexane/ethyl acetate, 7.7 g (58%) of thetitle compound is obtained.

¹H-NMR (CDCl₃): δ=0.03 (6H), 0.90 (9H), 1.85-2.00 (4H), 2.20-2.30 (2H),3.83 (2H), 9.70 (1H) ppm.

Cd)1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]-α-ethylcyclobutanemethanol

A solution of 7.7 g (33.7 mmol) of the compound, described under Cc), in80 ml of tetrahydrofuran is added in drops at 0° C. to 20 ml of a 2molar solution of ethylmagnesium chloride (40 mmol) in tetrahydrofuran.It is allowed to stir for 30 more minutes at 0° C., and then thereaction mixture is poured onto saturated ammonium chloride solution. Itis extracted with ethyl acetate. The organic phase is washed withsaturated sodium chloride solution and dried on sodium sulfate. Afterthe solvent is drawn off, the crude product that is obtained is purifiedby column chromatography on silica gel. 7.93 g (91.5%) of the titlecompound is obtained.

¹H-NMR (CDCl₃): δ=0.09 s (6H), 0.90 s (9H), 1.05 (3H), 1.30-1.50 (3H),1.70-1.90 (4H), 2.09 (1H), 3.19 (1H), 3.46 (1H), 3.72 (1H), 3.85 (1H)ppm.

Ce)1-[1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-methyl]cyclobut-1-yl]-1-propanone

6 ml (85.7 mmol) of dimethyl sulfoxide is added to 3.76 ml (43.8 mmol)of oxalyl chloride in 80 ml of dichloromethane at −78° C. It is allowedto stir for 3 more minutes, and then a solution of 7.93 g (30.7 mmol) ofthe compound, described under Cd), in 80 ml of dichloromethane is added.it is stirred for 15 more minutes at −78° C. Then, a mixture of 19 ml(136 mmol) of triethylamine and 40 ml of dichloromethane is added indrops. It is allowed to heat to −25° C. and stirred at this temperaturefor 30 more minutes. Then, the reaction mixture is poured onto saturatedice-cooled sodium bicarbonate solution. It is extracted withdichloromethane. The organic phase is washed with saturated sodiumchloride solution and dried on sodium sulfate. After the solvent isdrawn off, the crude product that is obtained is filtered on silica gel.7.87 g (100%) of the title compound is obtained.

¹H-NMR (CDCl₃): δ=0.05 (6H), 0.88 (9H), 1.04 (3H), 1.82-1.95 (4H),2.33-2.47 (2H), 2.45-2.54 (2H), 3.81 (2H) ppm.

Cf) 1-[1-(Hydroxymethyl)cyclobut-1-yl]-1-propanone

7.87 g (30.7 mmol) of the compound that is described under Ce) isdissolved in 100 ml of tetrahydrofuran. 15 ml of a 1 molar solution oftetrabutylammonium fluoride is added, and it is allowed to stir for 12more hours at 25° C. Then, the reaction mixture is poured onto saturatedsodium bicarbonate solution. It is extracted with ethyl acetate. Theorganic phase is washed with saturated sodium chloride solution anddried on sodium sulfate. After the solvent is drawn off, the crudeproduct that is obtained is purified by column chromatography on silicagel. 3.19 g (73.4%) of the title compound is obtained.

¹H-NMR (CDCl₃): δ=1.07 (3H), 1.86-2.08 (4H), 2.32-2.40 (2H), 2.55-2.65(2H), 3.88 (2H) ppm.

C) 1-(1-Oxopropyl)cyclobutanecarbaldehyde

Analogously to Example Ce), 3.14 g (100%) of the title compound isobtained by oxidation from 3.19 g (22.4 mmol) of the compound that isdescribed under Cf).

¹H-NMR (CDCl₃): δ=1.07 (3H), 1.85-2.00 (2H), 2.40-2.53 (6H), 9.70 (1H)ppm.

EXAMPLE 1(R)-4,4-Dimethyl-3-[3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-5-oxo-heptanoicacid

0.17 ml of a 30% hydrogen peroxide solution is added at 0° C. to asolution of 190 mg of the silyl ether, produced under Example 1c), in2.5 ml of a mixture of tetrahydrofuran and water at a 4:1 ratio. After 5minutes of stirring, a solution of 15.8 mg of lithium hydroxide in 0.83ml of water is then added, and the reaction mixture is stirred for 3hours at 25° C. Then, it is mixed with a solution of 208 mg of sodiumsulfite in 1.24 ml of water and extracted with 10 ml of methylenechloride. The aqueous phase is set at pH=1 with 5N hydrochloric acid andextracted three times with 10 ml of ethyl acetate each. After drying onsodium sulfate and filtration, it is concentrated by evaporation in avacuum. In addition, the above-mentioned methylene chloride phase iswashed with 5N hydrochloric acid, and then this aqueous phase isextracted three times with 10 ml of ethyl acetate each. After drying onsodium sulfate and filtration, it is concentrated by evaporation in avacuum, and an additional amount of crude product is obtained. Thecombined residues that are thus obtained are purified by chromatographyon silica gel. In addition to 70 mg of(4R,5S)-4-methyl-5-phenyloxazolidin-2-one, 93 mg of the title compoundis obtained with hexane/0-50% ethyl acetate as a colorless oil.[α]_(D)=+15.5° (CHCl₃)

¹H-NMR (CDCl₃): d=0.03-0.08 (6H), 0.86 (9H), 1.01 (3H), 1.10 (3H), 1.15(3H), 2.35 (1H), 2.4-2.7 (3H), 4.48 (1H) ppm.

1a) (4R,5S)-3-(Bromoacetyl)-4-methyl-5-phenyloxazolidin-2-one

117 ml of a 1.6 molar solution of butyllithium in hexane is added to asolution of 30.1 g of (4R,5S)-4-methyl-5-phenyloxazolidin-2-one in 500ml of tetrahydrofuran within 30 minutes at −70° C. under nitrogen. Then,a solution of 26.8 g of bromoacetyl chloride in 250 ml oftetrahydrofuran is added in drops in such a way that the temperaturedoes not exceed −65° C. After 1.75 hours of stirring at −70° C., asaturated ammonium chloride solution is added, followed by 60 ml of asaturated sodium bicarbonate solution, and it is allowed to come to 25°C. After the phases are separated, the aqueous phase is extracted twicewith 100 ml of ether each. The combined organic phases are washed withsemiconcentrated sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation in a vacuum after filtration. The residuethat is thus obtained is purified by chromatography on silica gel. Withhexane/0-50% ether, 34.8 g of the title compound is obtained as acolorless oil.

¹H-NMR (CDCl₃): δ=0.95 (3H), 4.57 (2H), 4.80 (2H), 5.76 (2H), 7.2-7.5(5H) ppm.

1b)[4R-[3(R*),4α,5α]]-3-[4,4-Dimethyl-1,5-dioxo-3-hydroxyheptyl]-4-methyl-5-phenyl-oxazolidin-2-one

218 mg of lithium iodide is added to a suspension of 5.0 g of anhydrouschromium(II) chloride in 60 ml of tetrahydrofuran under argon. Then, amixture of 2.09 g of the 2,2-dimethyl-3-oxo-pentanol that is known inthe literature (see under “Starting Products” Ab) and 5.34 g of theabove-produced bromine compound in 10 ml of tetrahydrofuran are added.After 2 hours of reaction time, it is mixed with 30 ml of saturatedsodium chloride solution and stirred for 15 minutes. The aqueous phaseis extracted three times with 200 ml of ether each. The combined organicphases are washed with semiconcentrated sodium chloride solution, driedon sodium sulfate and concentrated by evaporation in a vacuum afterfiltration. The residue that is thus obtained is purified bychromatography on silica gel. With hexane/0-30% ethyl acetate, 1.55 g ofthe title compound is obtained as a colorless oil.

¹H-NMR (CDCl₃): δ=0.92 (3H), 1.06 (3H), 1.18 (3H), 1.23 (3H), 2.58 (2H),3.07 (2H), 3.28 (1H), 4.35 (1H), 4.79 (1H), 5.70 (2H), 7.2-7.5 (5H) ppm.

1c)[4R-[3(R*),4α,5α]]-3-[4,4-Dimethyl-3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-1,5-dioxoheptyl]-4-methyl-5-phenyloxazolidin-2-one

150 mg of 2,6-lutidine is added to a solution of 347 mg of theabove-produced alcohol in 3 ml of methylene chloride under argon at −70°C. After 5 minutes of stirring, 344 mg oftert-butyldimethylsilyltrifluoromethane sulfonate is added, and it isstirred for another 45 minutes at −70° C. It is mixed with 1 ml ofsaturated sodium chloride solution and allowed to come to 25° C. Then,it is diluted with ether, and the organic phase is washed with saturatedsodium chloride solution. After drying on sodium sulfate and filtration,it is concentrated by evaporation in a vacuum. The residue that is thusobtained is purified by chromatography on silica gel. With hexane/0-30%ethyl acetate, 192 mg of the title compound is obtained as a colorlesscrystalline compound with a melting point of 111-112° C.

¹H-NMR (CDCl₃): δ=0.01-0.12 (6H), 0.86 (9H), 0.90 (3H), 1.00 (3H), 1.13(3H), 1.17 (3H), 2.56 (2H), 3.05 (2H), 4.65-4.80 (2H), 5.68 (1H),7.2-7.5 (5H) ppm.

EXAMPLE 2(S)-4,4-Dimethyl-3-[3-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-5-oxo-heptanoicacid

The compound is produced analogously to Example 1. As a startingproduct, (4S,5R)-4-methyl-5-phenyloxazolidin-2-one is used. The coverageof NMR is identical to Example 1. [α]_(D) =−15.7° (CHCl₃)

2a) (4S,5R)-3-(Bromoacetyl)-4-methyl-5-phenyloxazolidin-2-one

Production is carried out analogously to Example 1a) starting from(4S,5R)-4-methyl-5-phenyloxazolidin-2-one. The coverage of NMR isidentical to 1a).

EXAMPLE 3(S)-3-[3-[[Dimethyl(1,1-dimethyl)silyl]oxy]-3-[1-(1-oxopropyl)cyclobut-1-yl]propanoicAcid

1.49 g (80%) of the title compound and 941 mg of recovered(4S,5R)-4-methyl-5-phenyloxazolidin-2-one are obtained analogously toExample 1 from 2.79 g (5.9 mmol) of the compound that is described under3b). The title compound and the recovered chiral auxiliary can beseparated by chromatography (analogously to Example 1) or elsefractionated crystallization and then optionally purified bychromatography.

¹H-NMR (CDCl₃): δ=0.09 (3H), 0.19 (3H), 0.90 (9H), 1.08 (3H), 1.70-2.00(3H), 2.20-2.40 (4H), 2.47 (1H), 2.50-2.70 (2H), 4.45 (1H) ppm.

3a)[4S-[3(R*),4α,5α]]-3-[3-Hydroxy-1-oxo-3-[1-(1-oxopropyl)cyclobut-1-yl]propyl]-4-methyl-5-phenyloxazolidin-2-one

Analogously to Example 1b), 3.0 g (37.4%) of the title compound isobtained as a colorless oil from 3.14 g (22.4 mmol) of the compound thatis described under C), 9.7 g (78.8 mmol) of anhydrous chromium(II)chloride, 9.69 g (32.5 mmol) of 2a) and 300 mg (2.2 mmol) of anhydrouslithium iodide in tetrahydrofuran after column chromatography on silicagel.

¹H-NMR (CDCl₃): δ=0.93 (3H), 1.10 (3H), 1.80-2.03 (2H), 2.10-2.21 (1H),2.26-2.35 (3H), 2.54-2.70 (2H), 3.03-3.08 (2H), 3.34 (1H), 4.39 (1H),4.74-4.85 (1H), 5.69 (1H), 7.27-7.34 (2H), 7.36-7.49 (3H) ppm.

3b)[4S-[3(R*),4α,5α]]-3-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-1-oxo-3-[1-(1-oxopropyl)cyclobut-1-yl]propyl]-4-methyl-5-phenyloxazolidin-2-one

Analogously to Example 1c), 2.79 g (70.6%) of the title compound isobtained from 3.0 g (8.35 mmol) of the compound that is described underExample 3a), tert-butyldimethylsilyl-trifluoromethane sulfonate and2,6-lutidine after recrystallization from diisopropyl ether.

¹H-NMR (CDCl₃): δ=0.10 (3H), 0.21 (3H), 0.92 (3H), 0.95 (9H), 1.10 (3H),1.70-1.92 (2H), 2.02-2.16 (1H), 2.20-2.40 (3H), 2.50-2.72 (2H),2.98-3.10 (2H), 4.63-4.75 (1H), 5.69 (1H), 7.28-7.35 (2H), 7.36-7.48(3H) ppm.

EXAMPLE 4(R)-3-[3-[[Dimethyl(1,1-dimethyl)silyl]oxy]-3-[1-(1-oxopropyl)cyclobut-1-yl]propanoicAcid

The compound is produced analogously to Example 3. As a startingproduct, (4R,5S)-3-(bromoacetyl)-4-methyl-5-phenyloxazolidin-2-one isused.

The coverage of the NMR spectrum is identical to Example 3.

The stereochemistry in 3-position can be controlled by the selection ofthe stereochemistry at C4 and C5 of the chiral auxiliary4-methyl-5-phenyl-2-oxazolidone.

The structure of intermediate product 1b) was confirmed by an x-raystructural analysis.

EXAMPLES OF THE PRODUCTION OF COMPONENT C EXAMPLE 1(S)-Dihydro-3-hydroxy-2(3H)-furanone

10 g of L-(−)-malic acid is stirred in 45 ml of trifluoroacetic acidanhydride for 2 hours at 25° C. Then, it is concentrated by evaporationin a vacuum, 7 ml of methanol is added to the residue, and it is allowedto stir for 12 more hours. Then, it is concentrated by evaporation in avacuum. The residue that is obtained is dissolved in 150 ml of absolutetetrahydrofuran. It is cooled to 0° C., and 150 ml ofborane-tetrahydrofuran complex is added and allowed to stir for 2.5hours at 0° C. Then, 150 ml of methanol is added. It is allowed to stirfor one more hour at room temperature and then concentrated byevaporation in a vacuum. The crude product that is obtained is dissolvedin 80 ml of toluene. 5 g of Dowex® (activated, acidic) is added andrefluxed for one hour. Then, Dowex® is filtered off, and the filtrate isconcentrated by evaporation in a vacuum. The crude product that isobtained (7.61 g, 99.9%) is used without purification in the next step.

EXAMPLE 2(S)-Dihydro-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2(3H)-furanone

24 ml of tert-butyldiphenylsilyl chloride is added to a solution of 7.61g of the substance that is described under Example 1 and 10 g ofimidazole in 100 ml of N,N-dimethylformamide. It is allowed to stir fortwo more hours at 25° C., and then the reaction mixture is poured ontoice-cold saturated sodium bicarbonate solution. It is extracted withethyl acetate, the organic phase is washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. After column chromatography of the crudeproduct on silica gel with a mixture of hexane/ethyl acetate, 13.4 g(52.8%) of the title compound is obtained.

¹H-NMR (CDCl₃): δ=7.72 (2H), 7.70 (2H), 7.40-7.50 (6H), 4.30-4.42 (2H),4.01 (1H), 2.10-2.30 (2H), 1.11 (9H) ppm.

EXAMPLE 3(2RS,3S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]tetrahydro-2-furanol

80 ml of a 1 molar solution of diisobutylaluminum hydride in hexane isadded at −78° C. to a solution of 13.4 g of the substance, describedunder Example 2, in 150 ml of absolute tetrahydrofuran. It is stirredfor 45 more minutes at −78° C. and then quenched with water. It isextracted with ethyl acetate, the organic phase is washed with saturatedsodium chloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. 13.46 g (99.4%) of the title compound, which isused without purification in the next step, is obtained.

EXAMPLE 4(2RS,3S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-1,4-pentanediol

A solution of 13.46 g of the substance, described under Example 3, in150 ml of absolute tetrahydrofuran is added in drops to 20 ml of a 3molar solution of methylmagnesium chloride in tetrahydrofuran at 0° C.It is allowed to stir for one more hour at 0° C. and then poured ontosaturated aqueous ammonium chloride solution. It is extracted with ethylacetate, the organic phase is washed with saturated sodium chloridesolution, dried on sodium sulfate and concentrated by evaporation in avacuum. After column chromatography of the crude product on silica gelwith a mixture of hexane/ethyl acetate, 11.42 g (81.6%) of the titlecompound is obtained.

¹H-NMR (CDCl₃): δ=7.65-7.75 (4H), 7.40-7.55 (6H), 5.20 (1H), 4.30 (2H),3.70 (1H), 1.80 (2H), 1.05 (9H) ppm.

EXAMPLE 5(2RS,3S)-5-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-pentanol

4.9 g of tert-butyldimethylsilyl chloride is added to a solution of11.42 g of the substance that is described under Example 1ac, and 3.25 gof 1H-imidazole in 120 ml of N,N-dimethylformamide. It is allowed tostir for 2 more hours at 25° C., and then the reaction mixture is pouredonto ice-cold, saturated sodium bicarbonate solution. It is extractedwith ethyl acetate, the organic phase is washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. After column chromatography of the crudeproduct on silica gel with a mixture of hexane/ethyl acetate, 10.64 g(70.5%) of the title compound is obtained.

¹H-NMR (CDCl₃): δ=7.60-7.70 (4H), 7.30-7.45 (6H), 3.70-3.80 (2H), 3.40(1H), 3.00 (1H), 1.80 (1H), 1.60 (1H), 1.05-1.12 (12H), 0.82 (9H), 0.02(6H) ppm.

EXAMPLE 6(3S)-5-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-pentanone

13 ml of dimethyl sulfoxide is added to 7.37 ml of oxalyl chloride in 80ml of dichloromethane at −78° C. It is allowed to stir for 3 moreminutes, and then 10.46 g of the substance, described under Example 5,in 100 ml of dichloromethane, is added. After another 15 minutes ofstirring time, 52 ml of triethylamine is added in drops. Then, it isallowed to heat to 0° C. Then, the reaction mixture is poured ontosaturated sodium bicarbonate solution. It is extracted withdichloromethane, the organic phase is washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. After column chromatography of the crudeproduct on silica gel with a mixture of hexane/ethyl acetate, 9.3 g(26.5% relative to the malic acid that is used) of the title compound isobtained.

¹H-NMR (CDCl₃): δ=7.60-7.70 (4H), 7.32-7.50 (6H), 4.25 (1H), 3.72 (1H),3.58 (1H), 2.05 (3H), 1.90 (1H), 1.75 (1H), 1.13 (9H), 0.89 (9H), 0.01(6H) ppm.

EXAMPLE 7 (R)-Dihydro-3-hydroxy-2(3H)-furanone

10 g of D-(+)-malic acid is reacted analogously to Example 1. 7.26 g ofthe title compound is obtained. The coverage of the ¹H-NMR spectrum isidentical to 1.

EXAMPLE 8(R)-Dihydro-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2(3H)-furanone

Analogously to Example 2, 12.9 g of the title compound is obtained from7.26 g of the substance that is described under Example 7. The coverageof the 1H-NMR spectrum is identical to 2.

EXAMPLE 9(2RS,3R)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]tetrahydro-2-furanol

Analogously to Example 3, 12.95 g of the title compound is obtained from12.9 g of the substance that is described under Example 8. The coverageof the ¹H-NMR spectrum is identical to 3.

EXAMPLE 10(2RS,3R)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-1,4-pentanediol

Analogously to Example 4, 11 g of the title compound is obtained from12.95 g of the substance that is described under Example 9. The coverageof the ¹H-NMR spectrum is identical to 4.

EXAMPLE 11(2RS,3R)-5-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-pentanol

Analogously to Example 5, 10.11 g of the title compound is obtained from11 g of the substance that is described under Example 10. The coverageof the ¹H-NMR spectrum is identical to 5.

EXAMPLE 12(R)-5-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-pentanone

Analogously to Example 6, 8.85 g of the title compound is obtained from10.11 g of the substance that is described under Example 11. Thecoverage of the ¹H-NMR spectrum is identical to 6.

EXAMPLE 13 (3RS)-Dihydro-3-hydroxy-2(3H)-furanone

5 g of racemic malic acid is reacted analogously to Example 1. 3.68 g ofthe title compound is obtained. The coverage of the ¹H-NMR spectrum isidentical to 1.

EXAMPLE 14(3RS)-Dihydro-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2(3H)-furanone

Analogously to Example 2, 6.5 g of the title compound is obtained from3.68 g of the substance that is described under Example 13. The coverageof the ¹H-NMR spectrum is identical to 2.

EXAMPLE 15(2RS,3RS)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]tetrahydro-2-furanol

Analogously to Example 3, 6.51 g of the title compound is obtained from6.5 g of the substance that is described under Example 14. The coverageof the ¹H-NMR spectrum is identical to 15.

EXAMPLE 16(2RS,3RS)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-1,4-pentanediol

Analogously to Example 4, 5.5 g of the title compound is obtained from6.51 g of the substance that is described under Example 15. The coverageof the ¹H-NMR spectrum is identical to 4.

EXAMPLE 17(2RS,3RS)-5-[[Dimethyl(1,1-diethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-pentanol

Analogously to Example 5, 5.05 g of the title compound is obtained from5.5 g of the substance that is described under Example 16. The coverageof the ¹H-NMR spectrum is identical to 5.

EXAMPLE 18(3RS)-5-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-pentanone

Analogously to Example 6, 4.3 g of the title compound is obtained from5.05 g of the substance that is described under Example 17. The coverageof the ¹H-NMR spectrum is identical to 6.

EXAMPLE 19(E,3S)-1-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-ene

The solution of 6.82 g ofdiethyl(2-methylthiazol-4-yl)methanephosphonate in 300 ml of anhydroustetrahydrofuran is cooled under an atmosphere of dry argon to −5° C.,mixed with 16.2 ml of a 1.6 molar solution of n-butyllithium inn-hexane, allowed to heat to 23° C. and stirred for 2 hours. Then, it iscooled to −78° C., the solution of 6.44 g (13.68 mmol) of the compound,presented according to Example 6, in 150 ml of tetrahydrofuran is addedin drops, allowed to heat to 23° C. and stirred for 16 hours. It ispoured into saturated ammonium chloride solution, extracted severaltimes with ethyl acetate, the combined organic extracts are washed withsaturated sodium chloride solution and dried on sodium sulfate. Theresidue that is obtained after filtration and removal of the solvent ispurified by chromatography on fine silica gel with a gradient systemthat consists of n-hexane and ethyl acetate. 6.46 g (11.4 mmol, 83%;yield relative to the malic acid that is used: 22%) of the titlecompound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=−0.04 (6H), 0.83 (9H), 1.10 (9H), 1.79 (1H), 1.90(1H), 1.97 (3H), 2.51 (3H), 3.51 (2H), 4.38 (1H), 6.22 (1H), 6.74 (1H),7.23-7.47 (6H), 7.63 (2H), 7.70 (2H) ppm.

EXAMPLE 20(E,3S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-en-1-ol

The solution of 4.79 g (8.46 mmol) of the compound, presented accordingto Example 19, in 48 ml of tetrahydrofuran is mixed with 48 ml of a65:35:10 mixture of glacial acetic acid/water/tetrahydrofuran, and it isstirred for 2.5 days at 23° C. It is poured into saturated sodiumcarbonate solution, extracted several times with ethyl acetate, thecombined organic extracts are washed with saturated sodium chloridesolution and dried on sodium sulfate. The residue that is obtained afterfiltration and removal of the solvent is purified by chromatography onfine silica gel with a gradient system that consists of n-hexane andethyl acetate. 3.42 g (7.57 mmol, 90%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=1.10 (9H), 1.53 (1H), 1.81 (2H), 1.96 (3H), 2.71 (3H),3.59 (2H), 4.41 (1H), 6.38 (1H), 6.78 (1H), 7.26-7.49 (6H), 7.65 (2H),7.72 (2H) ppm.

EXAMPLE 21(E,3S)-1-Bromo-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-ene

The solution of 378 mg (0.84 mmol) of the compound, presented accordingto Example 20, in 9 ml of dichloromethane is mixed at 0° C. under anatmosphere of dry argon with 90 μl of pyridine, 439 mg oftriphenylphosphine, and 556 mg of tetrabromomethane, and it is stirredfor 1 hour at 0° C. The solution is chromatographed on fine silica gelwith a gradient system that consists of n-hexane and ethyl acetate. 362mg (0.70 mmol, 84%) of the title compound is isolated as a colorlessoil.

¹H-NMR (CDCl₃): δ=1.09 (9H), 1.95 (3H), 2.01-2.23 (2H), 2.71 (3H),3.15-3.35 (2H), 4.35 (1H), 6.30 (1H), 6.79 (1H), 7.25-7.49 (6H), 7.63(2H), 7.69 (2H) ppm.

EXAMPLE 22(E,3S)-1-Iodo-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-ene

The solution of 8.41 g of triphenylphosphine in 120 ml ofdichloromethane is mixed at 23° C. under an atmosphere of dry argon with2.19 g of imidazole and 8.14 g of iodine, the solution of 12.2 g (27.0mmol) of the compound, presented according to Example 20, in 30 ml ofdichloromethane is added in drops and stirred for 0.5 hour. The solutionis chromatographed on fine silica gel with a gradient system thatconsists of n-hexane and ethyl acetate. 12.15 g (21.6 mmol, 80%) of thetitle compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=1.08 (9H), 1.96 (3H), 2.10 (2H), 2.70 (3H), 2.87-3.08(2H), 4.24 (1H), 6.32 (1H), 6.79 (1H), 7.28-7.48 (6H), 7.60-7.72 (4H)ppm.

EXAMPLE 23(5E,3S)-[3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-en-1-yl]-triphenylphosphoniumiodide

The suspension of 12.55 g (22.3 mmol) of the compound that is presentedaccording to Example 22, 85 g of triphenylphosphine and 11.6 ml ofN-ethyldiisopropylamine is stirred under an atmosphere of dry argon for16 hours at 80° C. After cooling, it is mixed with diethyl ether,filtered, and the residue is rewashed several times with diethyl etherand recrystallized from ethyl acetate. 15.7 g (19.1 mmol, 74%) of thetitle compound is isolated as a crystalline solid.

¹H-NMR (CDCl₃): δ=1.07 (9H), 1.68-1.92 (2H), 1.98 (3H), 2.70 (3H), 2.93(1H), 3.30 (1H), 4.53 (1H), 6.62 (1H), 7.03 (1H), 7.23-7.47 (6H),7.48-7.72 (16H), 7.73-7.85 (3H) ppm.

EXAMPLE 24(E,3R)-1-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-ene

Analogously to Example 19, 8.56 g (80%) of the title compound isobtained from 8.85 g of the compound that is described under Example 12.The coverage of ¹H-NMR is identical to 19.

EXAMPLE 25(E,3R)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-en-1-ol

Analogously to Example 20, 6.25 g (92%) of the title compound isobtained from 8.56 g of the compound that is described under Example 24.The coverage of ¹H-NMR is identical to 20.

EXAMPLE 26(E,3R)-1-Iodo-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-ene

Analogously to Example 22, 6.22 g (80%) of the title compound isobtained from 6.25 g of the compound that is described under Example 25.The coverage of the ¹H-NMR spectrum is identical to 22.

EXAMPLE 27(5E,3R)-[3-[[(1,1-Dimethylethyl)-diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-en-1-yl]-triphenylphosphoniumIodide

Analogously to Example 23, 7.36 g (70%) of the title compound isobtained from 6.22 g of the compound that is described under Example 26.The coverage of the ¹H-NMR spectrum is identical to 23.

EXAMPLE 28(E,3RS)-1-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-ene

Analogously to Example 19, 4.52 g (87%) of the title compound isobtained from 4.3 g of the compound that is described under Example 18.The coverage of the ¹H-NMR spectrum is identical to 19.

EXAMPLE 29(E,3RS)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-en-1-ol

Analogously to Example 20, 3.16 g (88%) of the title compound isobtained from 4.52 g of the compound that is described under Example 28.The coverage of the ¹H-NMR spectrum is identical to 20.

EXAMPLE 30(E,3RS)-1-Iodo-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-ene

Analogously to Example 22, 3.34 g (85%) of the title compound isobtained from 3.16 g of the compound that is described under Example 25.The coverage of the ¹H-NMR spectrum is identical to 22.

EXAMPLE 31(5E,3RS)-[3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-en-1-yl]-triphenylphosphoniumIodide

Analogously to Example 23, 4.35 g (77%) of the title compound isobtained from 3.34 g of the compound that is described under Example 26.The coverage of the ¹H-NMR spectrum is identical to 23.

EXAMPLE 32(E,3S)-1-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-pyridyl)-pent-4-ene

Analogously to Example 19, 2 g (4.23 mmol) of the compound that ispresented according to Example 6 is reacted with use ofdiethyl(2-pyridyl)methanephosphonate, and after working-up andpurification, 2 g (3.68 mmol, 87%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=−0.06 (6H), 0.80 (9H), 1.09 (9H), 1.81 (1H), 1.90(1H), 2.00 (3H), 3.53 (2H), 4.40 (1H), 6.22 (1H), 6.99 (1H), 7.06 (1H),7.25-7.45 (6H), 7.58 (1H), 7.65-7.77 (4H), 8.58 (1H) ppm.

EXAMPLE 33(E,3S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-pyridyl)-pent-4-en-1-ol

Analogously to Example 20, 2 g (3.68 mmol) of the compound that isproduced under Example 32 is reacted with a 65:35:10 mixture of glacialacetic acid/water/tetrahydrofuran. After working-up, 1.38 g (3.20 mmol,87%) of the title compound is obtained.

¹H-NMR (CDCl₃): δ=1.12 (9H), 1.85 (2H), 2.00 (3H), 3.62 (2H), 4.5 (1H),6.44 (1H), 7.03 (1H), 7.08 (1H), 7.25-7.48 (6H), 7.59 (1H), 7.65-7.77(4H), 8.58 (1H) ppm.

EXAMPLE 34(Z,3S)-1-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(3-pyridyl)-pent-4-ene(A) and(E,3S)-1-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(3-pyridyl)-pent-4-ene(B)

Analogously to Example 19, 4.8 g (10.2 mmol) of the compound that ispresented according to Example 6 is reacted with use ofdiethyl(3-pyridyl)methanephosphonate, and after working-up andpurification, 448 mg (0.82 mmol, 8%) of title compound A and 3.5 g (6.41mmol, 63%) of title compound B are isolated in each case as a colorlessoil.

¹H-NMR (CDCl₃) of A: δ=−0.06 (6H), 0.81 (9H), 1.01 (9H), 1.75 (1H), 1.97(4H), 3.48 (2H), 4.83 (1H), 6.11 (1H), 6.97 (1H), 7.11-7.30 (5H),7.30-7.39 (2H), 7.39-7.50 (4H), 8.08 (1H), 8.33 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=−0.01 (6H), 0.85 (9H), 1.11 (9H), 1.78 (3H), 1.83(1H), 1.97 (1H), 3.58 (2H), 4.42 (1H), 6.03 (1H), 7.21 (1H), 7.28-7.50(7H), 7.62-7.75 (4H), 8.29 (1H), 8.41 (1H) ppm.

EXAMPLE 35(E,3S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(3-pyridyl)-pent-4-en-1-ol

Analogously to Example 20, 3.5 g (6.41 mmol) of the compound that isproduced under Example 34B is reacted with a 65:35:10 mixture of glacialacetic acid/water/tetrahydrofuran. After purification, 2.1 g (4.86 mmol,76%) is obtained.

¹H-NMR (CDCl₃): δ=1.12 (9H), 1.75 (3H), 1.88 (2H), 3.65 (2H), 4.45 (1H),6.25 (1H), 7.21 (1H), 7.28-7.50 (7H), 7.60-7.75 (4H), 8.30 (1H), 8.44(1H) ppm.

EXAMPLE 36

Analogously to Example 22, 1.98 g (75%) of the title compound isobtained from 2.1 g of the compound that is described under Example 35.

¹H-NMR (CDCl₃): δ=1.11 (9H), 1.78 (3H), 2.17 (2H), 3.03 (2H), 4.29 (1H),6.19 (1H), 7.22 (1H), 7.30-7.50 (7H), 7.63-7.75 (4H), 8.32 (1H), 8.44(1H) ppm.

EXAMPLE 37

Analogously to Example 23, 2.35 g (80%) of the title compound isobtained from 1.98 g of the compound that is described under Example 36.

¹H-NMR (CDCl₃): δ=1.08 (9H), 1.80 (3H), 3.27 (1H), 3.56 (1H), 4.66 (1H),6.52 (1H), 7.25-7.90 (27H), 8.35 (1H), 8.46 (1H) ppm.

EXAMPLE 38(Z,3S)-1-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(4-pyridyl)-pent-4-ene(A) and(E,3S)-1-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(4-pyridyl)-pent-4-ene(B)

Analogously to Example 19, 4.59 g (9.75 mmol) of the compound that isproduced according to Example 6 is reacted with use ofdiethyl(4-pyridyl)methanephosphonate, and after working-up andpurification, 605 mg (1.11 mmol, 11%) of title compound A and 4.34 g(7.95 mmol, 82%) of title compound B are isolated in each case as acolorless oil.

¹H-NMR (CDCl₃) of A: δ=−0.05 (6H), 0.82 (9H), 1.02 (9H), 1.78 (1H), 1.96(3H), 3.48 (2H), 4.92 (1H), 6.08 (1H), 6.73 (2H), 7.20-7.30 (4H),7.32-7.40 (2H), 7.41-7.49 (4H), 8.30 (2H) ppm.

¹H-NMR (CDCl₃) of B: δ=−0.04 (6H), 0.80 (9H), 1.08 (9H), 1.78 (3H), 1.91(1H), 3.55 (2H), 4.39 (1H), 6.02 (1H), 6.93 (2H), 7.26-7.48 (6H),7.60-7.72 (4H), 8.50 (2H) ppm.

EXAMPLE 39(E,3S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(4-pyridyl)-pent-4-en-1-ol

Analogously to Example 20, 4.34 g (7.95 mmol) of the compound that isproduced under Example 38B is reacted with a 65:35:10 mixture of glacialacetic acid/water/tetrahydrofuran. After purification, 2.92 g (6.76mmol, 85%) of the title compound is obtained.

¹H-NMR (CDCl₃): δ=1.12 (9H), 1.78 (3H), 1.87 (2H), 3.65 (2H), 4.42 (1H),6.26 (1H), 6.97 (2H), 7.26-7.48 (6H), 7.60-7.72 (4H), 8.52 (2H) ppm.

EXAMPLE 40

Analogously to Example 22, 2.82 g (77%) of the title compound isobtained from 2.92 g (6.76 mmol) of the compound that is described underExample 39.

¹H-NMR (CDCl₃): δ=1.08 (6H), 1.78 (3H), 2.15 (2H), 3.00 (2H), 4.26 (1H),6.17 (1H), 6.95 (2H), 7.30-7.50 (6H), 7.60-7.70 (4H), 8.50 (2H) ppm.

EXAMPLE 41

Analogously to Example 23, 3.27 g (4.06 mmol, 78%) of the title compoundis obtained from 2.82 g (5.21 mmol) of the compound that is describedunder Example 40.

¹H-NMR (CDCl₃): δ=1.09 (6H), 1.82 (3H), 3.15 (1H), 3.50 (1H), 4.65 (1H),6.53 (1H), 7.05 (2H), 7.25-7.48 (6H), 7.50-7.70 (4H), 8.50 (2H) ppm.

Production of the Epothilone Derivatives of General Formula I:

EXAMPLE 1(4S,7R,8S,9S,13(Z),16S(E))-4,8-Dihydroxy-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dioneEXAMPLE 1a(3S)-1-Oxa-2-oxo-3-(tetrahydropyran-2(RS)-yloxy)-4,4-dimethyl-cyclopentane

The solution of 74.1 g (569 mmol) of D-(−)-pantolactone in 1 l ofanhydrous dichloromethane is mixed with 102 ml of 3,4-dihydro-2H-pyranand 2 g of p-toluenesulfonic acid-pyridinium salt under an atmosphere ofdry argon, and it is stirred for 16 hours at 23° C. It is poured into asaturated sodium bicarbonate solution, and the organic phase isseparated and dried on sodium sulfate. After filtration and removal ofthe solvent, the residue is chromatographed on about 5 kg of fine silicagel with a mixture of n-hexane and ethyl acetate. 119.6 g (558 mmol,98%) of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃) δ=1.13 (3H), 1.22 (3H), 1.46-1.91 (6H), 3.50-3.61 (1H),3.86 (1H), 3.92 (1H), 4.01 (1H), 4.16 (1H), 5.16 (1H) ppm.

EXAMPLE 1b(2RS,3S)-1-Oxa-2-hydroxy-3-(tetrahydropyran-2(RS)-yloxy)-4,4-dimethyl-cyclopentane

The solution of 117.5 g (548 mmol) of the compound, presented accordingto Example 1a, in 2.4 l of anhydrous toluene is cooled under anatmosphere of dry argon to −70° C., mixed within 1 hour with 540 ml of a1.2 molar solution of diisobutyl aluminum hydride in toluene, and it isstirred for another 3 hours at −70° C. It is allowed to heat to −20° C.,mixed with saturated ammonium chloride solution and water, and theprecipitated aluminum salts are separated by filtration on Celite. Thefiltrate is washed with water and saturated sodium chloride solution anddried on magnesium sulfate. After filtration and removal of the solvent,111.4 g (515 mmol, 94%) of the title compound is isolated as a colorlessoil, which is further reacted without purification.

IR(CHCl₃): 3480, 3013, 2950, 2874, 1262, 1133, 1074, 1026 and 808 cm⁻¹.

EXAMPLE 1c(3S)-2,2-Dimethyl-3-(tetrahydropyran-2(R)-yloxy)-pent-4-en-1-ol and(3S)-2,2-dimethyl-3-(tetrahydropyran-2(S)-yloxy)-pent-4-en-1-ol

The suspension of 295 g of methyl-triphenylphosphonium bromide in 2.5 lof anhydrous tetrahydrofuran is mixed under an atmosphere of dry argonat −60° C. with 313 ml of a 2.4 molar solution of n-butyllithium inn-hexane, allowed to heat to 23° C., stirred for one more hour andcooled to 0° C. It is mixed with the solution of 66.2 g (306 mmol) ofthe compound, presented according to Example 1b, in 250 ml oftetrahydrofuran, allowed to heat to 23° C. and stirred for 18 hours. Itis poured into a saturated sodium bicarbonate solution, extractedseveral times with dichloromethane, and the combined organic extractsare dried on sodium sulfate. After filtration and removal of thesolvent, the residue is chromatographed on about 5 l of fine silica gelwith a gradient system that consists of n-hexane and ethyl acetate. 36.5g (170 mmol, 56%) of the nonpolar THP-isomer of the title compound, 14.4g (67.3 mmol, 22%) of the polar THP-isomer of the title compound, and7.2 g (33.3 mmol; 11%) of the starting material are isolated in eachcase as a colorless oil.

¹H-NMR (CDCl₃), nonpolar isomer: δ=0.78 (3H), 0.92 (3H), 1.41-1.58 (4H),1.63-1.87 (2H), 3.18 (1H), 3.41 (1H), 3.48 (1H), 3.68 (1H), 3.94 (1H),4.00 (1H), 4.43 (1H), 5.19 (1H), 5.27 (1H), 5.75 (1H) ppm.

¹H-NMR (CDCl₃), polar isomer: δ=0.83 (3H), 0.93 (3H), 1.42-1.87 (6H),2.76 (1H), 3.30 (1H), 3.45 (1H), 3.58 (1H), 3.83 (1H), 3.89 (1H), 4.65(1H), 5.12-5.27 (2H), 5.92 (1H) ppm.

EXAMPLE 1d(3S)-1-(tert-Butyldiphenylsilyloxy)-2,2-dimethyl-pentane-3-(tetrahydropyran-2-yloxy)-pent-4-ene

The solution of 59.3 g (277 mmol) of the THP-isomer mixture, presentedaccording to Example 1c, in 1000 ml of anhydrous dimethylformamide ismixed under an atmosphere of dry argon with 28 g of imidazole, 85 ml oftert-butyldiphenylchlorosilane, and it is stirred for 16 hours at 23° C.It is poured into water, extracted several times with dichloromethane,the combined organic extracts are washed with water and dried on sodiumsulfate. After filtration and removal of the solvent, the residue ischromatographed on fine silica gel with a gradient system that consistsof n-hexane and ethyl acetate. 106.7 g (236 mmol, 85%) of the titlecompound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.89 (3H), 0.99 (3H), 1.08 (9H), 1.34-1.82 (6H), 3.40(1H), 3.51 (2H), 3.76 (1H), 4.02 (1H), 4.67 (1H), 5.18 (1H), 5.23 (1H),5.68 (1H), 7.30-7.48 (6H), 7.60-7.73 (4H) ppm.

EXAMPLE 1e(3S)-1-(tert-Butyldiphenylsilyloxy)-2,2-dimethyl-3-(tetrahydropyran-2-yloxy)-pentan-5-ol

The solution of 3.09 g (6.83 mmol) of the compound, presented accordingto Example 1d, in 82 ml of tetrahydrofuran is mixed with 13.1 ml of a 1molar solution of borane in tetrahydrofuran under an atmosphere of dryargon at 23° C., and it is allowed to react for 1 hour. Then, whilebeing cooled with ice, it is mixed with 16.4 ml of a 5% sodium hydroxidesolution as well as 8.2 ml of a 30% hydrogen peroxide solution, and itis stirred for another 30 minutes. It is poured into water, extractedseveral times with ethyl acetate, the combined organic extracts arewashed with water and saturated sodium chloride solution and dried onmagnesium sulfate. The residue that is obtained after filtration andremoval of the solvent is purified by chromatography on fine silica gelwith a gradient system that consists of n-hexane and ethyl acetate. 1.78g (3.78 mmol, 55%) of the title compound is isolated as achromatographically separable mixture of the two THP-epimeres, as wellas 0.44 g (1.14 mmol, 17%) of the title compound of Example 6 in eachcase as a colorless oil.

¹H-NMR (CDCl₃), nonpolar THP-isomer: δ=0.80 (3H), 0.88 (3H), 1.10 (9H),1.18-1.80 (9H), 3.27 (1H), 3.39 (1H), 3.48 (1H), 3.64 (1H), 3.83 (1H),3.90-4.08 (2H), 4.49 (1H), 7.31-7.50 (6H), 7.58-7.73 (4H) ppm.

¹H-NMR (CDCl₃), polar THP-isomer: δ=0.89 (3H), 0.98 (3H), 1.08 (9H),1.36-1.60 (4H), 1.62-1.79 (3H), 1.88 (1H), 2.03 (1H), 3.37 (1H), 3.50(1H), 3.57 (1H), 3.62-3.83 (4H), 4.70 (1H), 7.30-7.48 (6H), 7.61-7.73(4H) ppm.

EXAMPLE 1f(3S)-1-(tert-Butyldiphenylsilyloxy)-2,2-dimethyl-3-hydroxy-pent-4-ene

The solution of 106.7 g (236 mmol) of the compound, presented accordingto Example 1d, in 1.5 l of anhydrous ethanol is mixed with 5.9 g ofpyridinium-p-toluenesulfonate under an atmosphere of dry argon, and itis heated for 6 hours to 50° C. After removal of the solvent, theresidue is chromatographed on fine silica gel with a mixture of n-hexaneand ethyl acetate. 82.6 g (224 mmol, 95%) of the title compound isisolated as a colorless oil, in which in addition about 5 g ofethoxy-tetrahydropyran is contained.

¹H-NMR (CDCl₃) of an analytic sample: δ=0.89 (6H), 1.08 (9H), 3.45 (1H),3.49 (1H), 3.58 (1H), 4.09 (1H), 5.21 (1H), 5.33 (1H), 5.93 (1H),7.34-7.51 (6H), 7.63-7.73 (4H) ppm.

EXAMPLE 1g(3S)-1-(tert-Butyldiphenylsilyloxy)-2,2-dimethyl-pentane-3,5-diol

Analogously to Example 1e, the solution of 570 mg (1.55 mmol) of thecompound that is presented according to Example 1f is reacted, and afterworking-up and purification, 410 mg (1.06 mmol, 68%) of the titlecompound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.82 (3H), 0.93 (3H), 1.08 (9H), 1.56-1.79 (2H), 3.11(1H), 3.50 (2H), 3.78-3.92 (3H), 4.02 (1H), 7.34-7.51 (6H), 7.61-7.71(4H) ppm.

EXAMPLE 1h4(S)-[2-Methyl-1-(tert-butyldiphenylsilyloxy)-prop-2-yl]-2,2-dimethyl-[1,3]dioxane

The solution of 100 mg (0.212 mmol) of the compounds, presentedaccording to Example 1e, in 2.6 ml of anhydrous acetone is mixed with78.9 mg of copper(II) sulfate, a spatula tip full of p-toluenesulfonicacid-monohydrate under an atmosphere of dry argon, and it is stirred for16 hours at 23° C. It is mixed with saturated sodium bicarbonatesolution, extracted several times with diethyl ether, washed withsaturated sodium chloride solution and dried on sodium sulfate. Theresidue that is obtained after filtration and removal of the solvent ispurified by chromatography on fine silica gel with a gradient systemthat consists of n-hexane and ethyl acetate. 24 mg (56 μmol, 27%) of thetitle compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.83 (3H), 0.89 (3H), 1.07 (9H), 1.30 (1H), 1.36 (3H),1.44 (3H), 1.71 (1H), 3.24 (1H), 3.62 (1H), 3.86 (1H), 3.91-4.03 (2H),7.31-7.48 (6H), 7.61-7.74 (4H) ppm.

Variant II

Analogously to Example 1h, 320 mg (0.88 mmol) of the compound that ispresented according to Example 1g is reacted; variant 1, and afterworking-up and purification, 234 mg (0.548 mmol, 62%) of the titlecompound is isolated.

Variant III

The solution of 5.60 g (14.5 mmol) of the compound, presented accordingto Example 1g, in 250 ml of anhydrous dichloromethane, is mixed with 10ml of 2,2-dimethoxypropane and 145 mg of camphor-10-sulfonic acid underan atmosphere of dry argon, and it is stirred for 6 hours at 23° C. Itis mixed with triethylamine, diluted with ethyl acetate, washed withsaturated sodium bicarbonate solution and dried on sodium sulfate. Afterfiltration and removal of the solvent, the residue is chromatographed onfine silica gel with a mixture of n-hexane and ethyl acetate. 5.52 g(12.9 mmol, 89%) of the title compound is isolated as a colorless oil.

EXAMPLE 1i(4S)-4-(2-Methyl-1-hydroxy-prop-2-yl)-2,2-dimethyl-[1,3]dioxane

The solution of 5.6 g (13.1 mmol) of the compound, presented accordingto Example 1h, in 75 ml of anhydrous tetrahydrofuran is mixed with 39 mlof a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuranunder an atmosphere of dry argon, and it is heated for 16 hours to 50°C. It is mixed with saturated sodium bicarbonate solution, extractedseveral times with ethyl acetate, washed with saturated sodium chloridesolution and dried on sodium sulfate. The residue that is obtained afterfiltration and removal of the solvent is purified by chromatography onfine silica gel with a gradient system that consists of n-hexane andethyl acetate. 2.43 g (12.9 mmol, 99%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.87 (3H), 0.90 (3H), 1.35 (1H), 1.37 (3H), 1.43 (3H),1.77 (1H), 2.93 (1H), 3.36 (1H), 3.53 (1H), 3.79 (1H), 3.87 (1H), 3.96(1H) ppm.

EXAMPLE 1k (4S)-4-(2-Methyl-1-oxo-prop-2-yl)-2,2-dimethyl-[1,3]dioxane

The solution of 0.13 ml of oxalyl chloride in 5.7 ml of anhydrousdichloromethane is cooled under an atmosphere of dry argon to −70° C.,mixed with 0.21 ml of dimethyl sulfoxide, the solution of 200 mg (1.06mmol) of the compound, presented according to Example 1i, in 5.7 ml ofanhydrous dichloromethane, and it is stirred for 0.5 hour. Then, it ismixed with 0.65 ml of triethylamine, allowed to react for 1 hour at −30°C. and mixed with n-hexane and saturated sodium bicarbonate solution.The organic phase is separated, the aqueous phase is extracted once morewith n-hexane, the combined organic extracts are washed with water anddried on magnesium sulfate. The residue that is obtained afterfiltration and removal of the solvent is further reacted withoutpurification.

EXAMPLE 1l(4S)-4-((3RS)-2-Methyl-3-hydroxy-hex-2-yl)-2,2-dimethyl-[1,3]dioxane

The solution of 450 mg (2.42 mmol) of the compound, presented accordingto Example 1k, in 7 ml of anhydrous diethyl ether is mixed with 1.21 mlof a 2.4 molar solution of propylmagnesium bromide in diethyl etherunder an atmosphere of dry argon at 0° C., allowed to heat to 23° C. andstirred for 16 hours. It is mixed with saturated ammonium chloridesolution, the organic phase is separated and dried on sodium sulfate.The residue that is obtained after filtration and removal of the solventis purified by chromatography on fine silica gel with a gradient systemthat consists of n-hexane and ethyl acetate. 244 mg (1.06 mmol, 44%) ofthe chromatographically separable 3R- and 3S-epimeres of the titlecompound as well as 191 mg of the title compound that is described inExample 1i are isolated in each case as a colorless oil.

¹H-NMR (CDCl₃) nonpolar isomer: δ=0.87 (3H), 0.89 (3H), 0.94 (3H),1.25-1.52 (4H), 1.38 (3H), 1.45 (3H), 1.66 (1H), 1.85 (1H), 3.46 (1H),3.80-4.02 (4H) ppm.

¹H-NMR (CDCl₃) polar isomer: δ=0.73 (3H), 0.92 (3H), 0.95 (3H),1.19-1.84 (6H), 1.37 (3H), 1.49 (3H), 3.49 (1H), 3.60 (1H), 3.80-4.03(3H) ppm.

EXAMPLE 1m (4S)-4-(2-Methyl-3-oxo-hex-2-yl)-2,2-dimethyl-[1,3]dioxane

The solution of 207 mg (0.90 mmol) of a mixture of the compound,presented according to Example 1l, in 18 ml of anhydrous dichloromethaneis mixed with molecular sieve (4A, about 20 spheres), 176 mg ofN-methylmorpholino-N-oxide and 18 mg of tetrapropylammoniumperruthenate, and it is stirred for 16 hours at 23° C. under anatmosphere of dry argon. It is concentrated by evaporation, and thecrude product that is obtained is purified by chromatography on about100 ml of fine silica gel with a gradient system that consists ofn-hexane and ethyl acetate. 185 mg (0.81 mmol, 90%) of the titlecompound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.88 (3H), 1.04 (3H), 1.12 (3H), 1.22-1.37 (1H), 1.31(3H), 1.40 (3H), 1.48-1.71 (3H), 2.46 (2H), 3.83 (1H), 3.96 (1H), 4.04(1H) ppm.

EXAMPLE 1n 4-Tert-butyldimethylsilyloxy-but-2-in-1-ol

A solution of 175 g of tert-butyldimethylsilyl chloride in 100 ml of a1:1 mixture of hexane and dimethylformamide is slowly added in drops toa solution of 100 g of 2-butin-1-ol and 158 g of imidazole in 300 ml ofdimethylformamide at 0° C. under nitrogen, and it is stirred for 2 hoursat 0° C. and for 16 hours at 22° C. The reaction mixture is diluted with2.5 l of ether, washed once with water, once with 5% sulfuric acid, oncewith water, once with saturated sodium bicarbonate solution and washedneutral with semi-saturated sodium chloride solution. After drying onsodium sulfate and filtration, it is concentrated by evaporation in avacuum. The residue that is thus obtained is purified by chromatographyon silica gel. 74.3 g of the title compound is obtained withhexane/0-40% ether as a colorless oil.

IR (film): 3357, 2929, 2858, 1472, 1362, 1255, 1132, 1083, 1015, 837,778 cm⁻¹.

EXAMPLE 1o(4R,5S,2′S)-4-Methyl-5-phenyl-3-[1-oxo-2-methyl-6-(tert-butyldimethylsilyloxy)-hex-4-in-1-yl]-2-oxazolidinone

11.3 ml of lutidine is added to 21 g of a solution of silyl ether,produced according to Example 1n, in 125 ml of toluene under nitrogen.Then, it is cooled to −40° C., and 17.7 ml of trifluoromethanesulfonicacid anhydride is added in drops at this temperature. Then, it isdiluted with 100 ml of hexane and stirred for 10 minutes. Under nitrogenvia a reversing frit, this solution is added to a solution that wasproduced from 17.8 g of hexamethyldisilazane in 140 ml oftetrahydrofuran with 73.5 ml of a 1.6 M solution of butyllithium inhexane at −60° C. (10 more minutes of stirring time) and 23.3 g of(4R,5S)-4-methyl-5-phenyl-3-propionyl-2-oxazolidinone in 62 ml oftetrahydrofuran (30 more minutes of stirring time). It is allowed tostir for one more hour at −60° C., then mixed with 6 ml of acetic acidin 5 ml of tetrahydrofuran, and the reaction mixture is allowed to heatto 22° C. It is added to 80 ml of water and extracted three times withether. The combined organic phases are washed twice with saturatedsodium chloride solution and dried on sodium sulfate. After filtration,it is concentrated by evaporation in a vacuum. The residue that is thusobtained is purified by chromatography on silica gel. With hexane/0-20%ether, 16.0 g of the title compound is obtained as a colorless oil.

¹H-NMR (CDCl₃): δ=0.10 (6H), 0.90 (9H), 0.92 (3H), 1.28 (3H), 2.47 (1H),2.61 (1H), 3.96 (1H), 4.26 (2H), 4.78 (1H), 5.68 (1H), 7.31 (1H),7.3-7.5 (3H) ppm.

EXAMPLE 1p (2S)-2-Methyl-6-(tert-butyldimethylsilyloxy)-4-hexinoic AcidEthyl Ester

9.0 ml of titanium(IV)ethylate is added to a solution of 39.3 g of thealkylating product, produced according to Example 1o, in 120 ml ofethanol under nitrogen, and it is refluxed for 4 hours. The reactionmixture is concentrated by evaporation in a vacuum, and the residue isdissolved in 100 ml of ethyl acetate. 3 ml of water is added, stirredfor 20 minutes, precipitate is suctioned out, and it is rewashed wellwith ethyl acetate. The filtrate is concentrated by evaporation, mixedwith 200 ml of hexane, and precipitate is filtered out. The precipitateis washed well with hexane. The filtrate is concentrated by evaporationin a vacuum, and the residue that is thus obtained is purified bychromatography on silica gel. With hexane/0-20% ether, 25.4 g of thetitle compound is obtained as a colorless oil.

¹H-NMR (CD₂Cl₂): δ=0.10 (3H), 0.90 (9H), 1.2-1.3 (6H), 2.37 (1H), 2.54(1H), 2.60 (1H), 4.12 (2H), 4.27 (2H) ppm.

EXAMPLE 1q (2S)-2-Methyl-6-(tert-butyldimethylsilyloxy)-hexanoic AcidEthyl Ester

A solution of 10.5 g of the ester, produced according to Example 1p, in200 ml of ethyl acetate is mixed with 1 g of 10% palladium on carbon,and it is stirred for 3 hours at 22° C. in a hydrogen atmosphere. Then,catalyst is filtered out, it is rewashed well with ethyl acetate, andthe filtrate is concentrated by evaporation in a vacuum. The residuethat is thus obtained is purified by chromatography on silica gel. Withhexane/0-10% ether, 9.95 g of the title compound is obtained as acolorless oil.

¹H-NMR (CD₂Cl₂): δ=0.01 (6H), 0.84 (9H), 1.07 (3H), 1.18 (3H), 1.2-1.7(6H), 2.38 (1H), 3.57 (2H), 4.05 (2H) ppm.

EXAMPLE 1r (2S)-2-Methyl-6-(tert-butyldimethylsilyloxy)-hexan-1-ol

63 ml of a 1.2 M solution of diisobutylaluminum hydride in toluene isadded to a solution of 9.94 g of the ester, produced according toExample 1q, in 130 ml of toluene at −40° C. under nitrogen, and it isstirred for 1 hour at this temperature. Then, 15 ml of isopropanol iscarefully added, and after 10 minutes, 30 ml of water is added, allowedto come to 22° C., and it is stirred at this temperature for 2 hours.Precipitate is filtered out, it is rewashed well with ethyl acetate, andthe filtrate is concentrated by evaporation in a vacuum. The residuethat is thus obtained is purified by chromatography on silica gel. Withhexane/0-30% ether, 7.9 g of the title compound is obtained as acolorless oil. [α]_(D)−8.1° (c=0.97, CHCl₃)

¹H-NMR (CDCl₃): δ=0.07 (3H), 0.89 (9H), 0.91 (3H), 1.0-1.7 (7H), 3.48(2H), 3.52 (2H) ppm.

EXAMPLE 1s(2S)-2-Methyl-6-(tert-butyldimethylsilyloxy)-1-(tetrahydro-2H-pyran-2-yloxy)-hexane

3.52 ml of dihydropyran, followed by 49 mg of p-toluenesulfonicacid-monohydrate, is added to 6.4 g of the alcohol, produced accordingto Example 1r, in 26 ml of methylene chloride at 0° C. under argon.After 1.5 hours of stirring at 0° C., it is mixed with 10 ml ofsaturated sodium bicarbonate solution and diluted with ether. Theorganic phase is washed twice with semi-saturated sodium chloridesolution and dried on sodium sulfate. After filtration, it isconcentrated by evaporation in a vacuum, and the residue that is thusobtained is purified by chromatography on silica gel. With hexane/0-5%ether, 4.75 g of the title compound is obtained as a colorless oil.

¹H-NMR (CDCl₃): δ=0.05 (6H), 0.89 (9H), 0.92 (3H), 1.0-1.9 (13H), 3.19(1H), 3.50 (1H), 3.55-3.65 (3H), 4.87 (1H), 4.57 (1H) ppm.

EXAMPLE 1t (5S)-5-Methyl-6-(tetrahydro-2H-pyran-2-yloxy)-hexan-1-ol

13.5 g of tetrabutylammonium fluoride trihydrate is added to a solutionof 4.7 g of the THP-ether, produced according to Example 1s, in 170 mlof tetrahydrofuran, under nitrogen, and it is stirred for 3 hours. Then,the reaction mixture is diluted with 800 ml of ether, and it is washedthree times each with 20 ml of semi-saturated sodium chloride solutionand dried on sodium sulfate. After filtration, it is concentrated byevaporation in a vacuum, and the residue that is thus obtained ispurified by chromatography on silica gel. With hexane/0-50% ethylacetate, 2.88 g of the title compound is obtained as a colorless oil.

¹H-NMR (CD₂Cl₂): δ=0.90/0.92 (3H), 1.1-1.9 (13H), 3.18 (1H), 3.40-3.65(4H), 3.82 (1H), 4.53 (1H) ppm.

EXAMPLE 1u (5S)-5-Methyl-6-(tetrahydro-2H-pyran-2-yloxy)-hexanal

1.9 ml of dimethyl sulfoxide, dissolved in 7 ml of methylene chloride,is carefully added in drops to 1.08 ml of oxalyl chloride, dissolved in10 ml of methylene chloride, under nitrogen at −70° C., and it isstirred for 10 minutes at this temperature. Then, a solution of 2.0 g ofthe alcohol, produced according to Example 1t, in 7 ml of methylenechloride is added in drops, and it is stirred for 2 hours between −60°C. and −70° C. Then, 3.86 ml of triethylamine is added, and after 1 hourof stirring at −60° C., the reaction mixture is added to 30 ml of water.After phase separation, the aqueous phase is extracted twice with 30 mlof methylene chloride each. The combined organic phases are washed threetimes with saturated sodium chloride solution. After drying on sodiumsulfate and filtration, it is concentrated by evaporation in a vacuum.1.99 g of the aldehyde, which is used without further purification, isobtained.

EXAMPLE 1v (2RS,6S)-6-Methyl-7-(tetrahydro-2H-pyran-2-yloxy)-heptan-2-ol

6.16 ml of a 3 M methylmagnesium bromide solution in ether is slowlyadded in drops to a solution of 1.98 g of the aldehyde, producedaccording to Example 1u, in 30 ml of ether under nitrogen at 0° C. After60 minutes, it is slowly poured onto 50 ml of ice-cold saturatedammonium chloride solution and extracted three times with ether. Thecombined organic phases are washed once with water, and twice withsaturated sodium chloride solution and dried on sodium sulfate. Afterfiltration, it is concentrated by evaporation in a vacuum, and theresidue that is thus obtained is purified by chromatography on silicagel. With hexane/0-60% ether, 1.57 g of the title compound is obtainedas a colorless oil.

¹H-NMR (CD₂Cl₂): δ=0.90/0.93 (3H), 1.15 (3H), 1.0-1.9 (13H), 3.18 (1H),3.4-3.6 (2H), 3.7-3.9 (2H), 4.53 (1H) ppm.

EXAMPLE 1w(2S,6RS)-2-Methyl-6-(tert-butyl-diphenylsilyloxy)-1-(tetrahydro-2H-pyran-2-yloxy)-heptane

2.13 ml of tert-butyldiphenylsilyl chloride is added to a solution of1.57 g of alcohol, produced according to Example 1v, and 1.11 g ofimidazole in 20 ml of dimethylformamide at 0° C. under nitrogen, and itis stirred for 15 minutes at 0° C. and for 16 hours at 22° C. Thereaction mixture is diluted with 200 ml of ether, washed once withwater, once with 10% sulfuric acid, once with saturated sodiumbicarbonate solution and washed neutral with saturated sodium chloridesolution. After drying on sodium sulfate and filtration, it isconcentrated by evaporation in a vacuum. The residue that is thusobtained is purified by chromatography on silica gel. With hexane/0-10%ether, 2.87 g of the title compound is obtained as a colorless oil.

¹H-NMR (CDCl₃): δ=0.87/0.89 (3H), 1.04 (9H), 0.9-1.9 (16H), 3.15 (1H),3.4-3.6 (2H), 3.8-3.9 (2H), 4.56 (1H), 7.3-7.5 (6H), 7.69 (4H) ppm.

EXAMPLE 1x (2S,6RS)-2-Methyl-6-(tert-butyl-diphenylsilyloxy)-heptan-1-ol

131 mg of pyridinium-p-toluenesulfonate is added to a solution of 2.3 gof silyl ether, produced according to Example 1w, in 100 ml of ethanol,and it is stirred for 4 hours at 40° C. Then, it is concentrated byevaporation in a vacuum, and the residue that is thus obtained ispurified by chromatography on silica gel. With hexane/20% ether, 1.68 gof the title compound is obtained as a colorless oil.

EXAMPLE 1y (2S,6RS)-2-Methyl-6-(tert-butyl-diphenylsilyloxy)-heptanal

Analogously to Example 1u, 2.13 g of the alcohol that is presented underExample 1x is oxidized, and after working-up and chromatographicpurification, 2.10 g of the title compound is isolated as a colorlessoil.

¹H-NMR (CDCl₃): δ=1.00-1.12 (15H), 1.18-1.63 (6H), 2.22 (1H), 3.83 (1H),7.32-7.47 (6H), 7.61-7.72 (4H), 9.54 (1H) ppm.

EXAMPLE 1z (S)-Dihydro-3-hydroxy-2(3H)-furanone

10 g of L-(−)-malic acid is stirred in 45 ml of trifluoroacetic acidanhydride for 2 hours at 25° C. Then, it is concentrated by evaporationin a vacuum, 7 ml of methanol is added to the residue and allowed tostir for 12 more hours. Then, it is concentrated by evaporation in avacuum. The residue that is obtained is dissolved in 150 ml of absolutetetrahydrofuran. It is cooled to 0° C., and 150 ml ofborane-tetrahydrofuran complex is added and allowed to stir for 2.5hours at 0° C. Then, 150 ml of methanol is added. It is allowed to stirfor one more hour at room temperature and then concentrated byevaporation in a vacuum. The crude product that is obtained is dissolvedin 80 ml of toluene. 5 g of Dowex### (activated, acidic) is added andrefluxed for one hour. Then, Dowex### is filtered off, and the filtrateis concentrated by evaporation in a vacuum. The crude product that isobtained (7.61 g) is used without purification in the next step.

EXAMPLE 1aa(S)-Dihydro-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2(3H)-furanone

24 ml of tert-butyldiphenylsilyl chloride is added to a solution of 7.61g of the substance that is described under Example 1z and 10 g ofimidazole in 100 ml of N,N-dimethylformamide. It is allowed to stir fortwo more hours at 25° C., and then the reaction mixture is poured ontoice-cold saturated sodium bicarbonate solution. It is extracted withethyl acetate, the organic phase is washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. After column chromatography of the crudeproduct on silica gel with a mixture of hexane/ethyl acetate, 13.4 g ofthe title compound is obtained.

¹H-NMR (CDCl₃): δ=7.72 (2H), 7.70 (2H), 7.40-7.50 (6H), 4.30-4.42 (2H),4.01 (1H), 2.10-2.30 (2H), 1.11 (9H) ppm.

EXAMPLE 1ab(2RS,3S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]tetrahydro-2-furanol

80 ml of a 1 molar solution of diisobutylaluminum hydride in hexane isadded at −78° C. to a solution of 13.4 g of the substance, describedunder Example 1aa, in 150 ml of absolute tetrahydrofuran. It is stirredfor 45 more minutes at −78° C. and then quenched with water. It isextracted with ethyl acetate, the organic phase is washed with saturatedsodium chloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. 13.46 g of the title compound, which is usedwithout purification in the next step, is obtained.

EXAMPLE 1ac(2RS,3S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-1,4-pentanediol

A solution of 13.46 g of the substance, described under Example 1ab, in150 ml of absolute tetrahydrofuran is added in drops to 20 ml of a 3molar solution of methylmagnesium chloride in tetrahydrofuran at 0° C.It is allowed to stir for one more hour at 0° C. and then poured ontosaturated aqueous ammonium chloride solution. It is extracted with ethylacetate, the organic phase is washed with saturated sodium chloridesolution, dried on sodium sulfate and concentrated by evaporation in avacuum. After column chromatography of the crude product on silica gelwith a mixture of hexane/ethyl acetate, 11.42 g of the title compound isobtained.

¹H-NMR (CDCl₃): δ=7.65-7.75 (4H), 7.40-7.55 (6H), 5.20 (1H), 4.30 (2H),3.70 (1H), 1.80 (2H), 1.05 (9H) ppm.

EXAMPLE 1ad(2RS,3S)-5-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-pentanol

4.9 g of tert-butyldimethylsilyl chloride is added to a solution of11.42 g of the substance that is described under Example 1ac, and 3.25 gof 1H-imidazole in 120 ml of N,N-dimethylformamide. It is allowed tostir for 2 more hours at 25° C., and then the reaction mixture is pouredonto ice-cold, saturated sodium bicarbonate solution. It is extractedwith ethyl acetate, the organic phase is washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. After column chromatography of the crudeproduct on silica gel with a mixture of hexane/ethyl acetate, 10.64 g ofthe title compound is obtained.

¹H-NMR (CDCl₃): δ=7.60-7.70 (4H), 7.30-7.45 (6H), 3.70-3.80 (2H), 3.40(1H), 3.00 (1H), 1.80 (1H), 1.60 (1H), 1.05-1.12 (12H), 0.82 (9H), 0.02(6H) ppm.

EXAMPLE 1ae(3S)-5-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-2-pentanone

13 ml of dimethyl sulfoxide is added to 7.37 ml of oxalyl chloride in 80ml of dichloromethane at −78° C. It is allowed to stir for 3 moreminutes, and then 10.46 g of the substance, described under Example 1ad,in 100 ml of dichloromethane, is added. After another 15 minutes ofstirring time, 52 ml of triethylamine is added in drops. Then, it isallowed to heat to 0° C. Then, the reaction mixture is poured ontosaturated sodium bicarbonate solution. It is extracted withdichloromethane, the organic phase is washed with saturated sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. After column chromatography of the crudeproduct on silica gel with a mixture of hexane/ethyl acetate, 9.3 g ofthe title compound is obtained.

¹H-NMR (CDCl₃): δ=7.60-7.70 (4H), 7.32-7.50 (6H), 4.25 (1H), 3.72 (1H),3.58 (1H), 2.05 (3H), 1.90 (1H), 1.75 (1H), 1.13 (9H), 0.89 (9H), 0.01(6H) ppm.

EXAMPLE 1af(E,3S)-1-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-ene

The solution of 6.82 g ofdiethyl(2-methylthiazol-4-yl)methanephosphonate in 300 ml of anhydroustetrahydrofuran is cooled under an atmosphere of dry argon to −5° C.,mixed with 16.2 ml of a 1.6 molar solution of n-butyllithium inn-hexane, allowed to heat to 23° C. and stirred for 2 hours. Then, it iscooled to −78° C., the solution of 6.44 g (13.68 mmol) of the compound,presented according to Example 1ae, in 150 ml of tetrahydrofuran isadded in drops, allowed to heat to 23° C. and stirred for 16 hours. Itis poured into saturated ammonium chloride solution, extracted severaltimes with ethyl acetate, the combined organic extracts are washed withsaturated sodium chloride solution and dried on sodium sulfate. Theresidue that is obtained after filtration and removal of the solvent ispurified by chromatography on fine silica gel with a gradient systemthat consists of n-hexane and ethyl acetate. 6.46 g (11.4 mmol, 83%) ofthe title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=−0.04 (6H), 0.83 (9H), 1.10 (9H), 1.79 (1H), 1.90(1H), 1.97 (3H), 2.51 (3H), 3.51 (2H), 4.38 (1H), 6.22 (1H), 6.74 (1H),7.23-7.47 (6H), 7.63 (2H), 7.70 (2H) ppm.

EXAMPLE 1ag(E,3S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-en-1-ol

The solution of 4.79 g (8.46 mmol) of the compound, presented accordingto Example 1af, in 48 ml of tetrahydrofuran is mixed with 48 ml of a65:35:10 mixture of glacial acetic acid/water/tetrahydrofuran andstirred for 2.5 days at 23° C. It is poured into saturated sodiumcarbonate solution, extracted several times with ethyl acetate, thecombined organic extracts are washed with saturated sodium chloridesolution and dried on sodium sulfate. The residue that is obtained afterfiltration and removal of the solvent is purified by chromatography onfine silica gel with a gradient system that consists of n-hexane andethyl acetate. 3.42 g (7.57 mmol, 90%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃) δ=1.10 (9H), 1.53 (1H), 1.81 (2H), 1.96 (3H), 2.71 (3H),3.59 (2H), 4.41 (1H), 6.38 (1H), 6.78 (1H), 7.26-7.49 (6H), 7.65 (2H),7.72 (2H) ppm.

EXAMPLE 1ah(E,3S)-1-Iodo-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-ene

The solution of 8.41 g of triphenylphosphine in 120 ml ofdichloromethane is mixed at 23° C. under an atmosphere of dry argon with2.19 g of imidazole, 8.14 g of iodine, the solution of 12.2 g (27.0mmol) of the compound, presented according to Example 1ag, in 30 ml ofdichloromethane is added in drops and stirred for 0.5 hour. The solutionis chromatographed on fine silica gel with a gradient system thatconsists of n-hexane and ethyl acetate. 12.15 g (21.6 mmol, 80%) of thetitle compound is isolated as a colorless oil.

¹H-NMR (CDCl₃) δ=1.08 (9H), 1.96 (3H), 2.10 (2H), 2.70 (3H), 2.87-3.08(2H), 4.24 (1H), 6.32 (1H), 6.79 (1H), 7.28-7.48 (6H), 7.60-7.72 (4H)ppm.

EXAMPLE 1ai(5E,3S)-[3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-en-1-yl]-triphenylphosphoniumiodide

The suspension of 12.55 g (22.3 mmol) of the compound that is presentedaccording to Example 1ah, 85 g of triphenylphosphine and 11.6 ml ofN-ethyldiisopropylamine is stirred under an atmosphere of dry argon for16 hours at 80° C. After cooling, it is mixed with diethyl ether,filtered, and the residue is rewashed several times with diethyl etherand recrystallized from ethyl acetate. 15.7 g (19.1 mmol, 74%) of thetitle compound is isolated as a crystalline solid.

¹H-NMR (CDCl₃): δ=1.07 (9H), 1.68-1.92 (2H), 1.98 (3H), 2.70 (3H), 2.93(1H), 3.30 (1H), 4.53 (1H), 6.62 (1H), 7.03 (1H), 7.23-7.47 (6H),7.48-7.72 (16H), 7.73-7.85 (3H) ppm.

EXAMPLE 1ak(4S(4R,5S,6S,10RS))-4-(2,6-Dimethyl-10-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-ethyl-5-hydroxy-3-oxo-undec-2-yl)-2,2-dimethyl-[1,3]dioxane(A) and(4S(4S,5R,6S,10RS))-4-(2,6-dimethyl-10-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-ethyl-5-hydroxy-3-oxo-undec-2-yl)-2,2-dimethyl-[1,3]dioxane(B)

The solution of 1.96 ml of diisopropylamine in 44 ml of anhydroustetrahydrofuran is cooled under an atmosphere of dry argon to −30° C.,mixed with 6.28 ml of a 2.4 molar solution of n-butyllithium in n-hexaneand stirred for 15 more minutes. At −78° C., the solution of 3.08 g(13.47 mmol) of the compound, presented according to Example 1m, in 44ml of tetrahydrofuran is added in drops, and it is allowed to react for1 hour. Then, it is mixed with the solution of 5.77 g (15.1 mmol) of thecompound, presented according to Example 1y, in 44 ml of tetrahydrofuranand poured after 45 minutes into saturated ammonium chloride solution.It is diluted with water, extracted several times with ethyl acetate,the combined organic extracts are washed with saturated sodium chloridesolution, dried on sodium sulfate and concentrated by evaporation in avacuum. After column chromatography on silica gel with a gradient systemthat consists of n-hexane and ethyl acetate, in addition to 13% startingmaterial, 4.03 g (5.92 mmol, 44%) of title compound A and 1.58 g (2.32mmol, 17%) of a diastereomer B are obtained.

¹H-NMR (CDCl₃) of A: δ=0.79 (3H) 0.85 (3H), 0.90-1.10 (16H), 1.19-1.79(10H), 1.26 (3H), 1.32 (3H), 1.38 (3H), 2.79 (1H), 3.18 (1H), 3.42 (1H),3.78-3.92 (2H), 3.98 (1H), 4.17 (1H), 7.30-7.46 (6H), 7.62-7.72 (4H)ppm.

¹H-NMR (CDCl₃) of B: δ=0.83 (3H), 0.91 (3H), 0.94-1.12 (16H), 1.19 (3H),1.15-1.80 (10H), 1.31 (3H), 1.41 (3H), 2.54 (1H), 3.18 (1H), 3.47 (1H),3.78-3.91 (2H), 3.97 (1H), 4.14 (1H), 7.31-7.47 (6H), 7.62-7.73 (4H)ppm.

EXAMPLE 1al(4S(4R,5S,6S,10RS))-4-(2,6-Dimethyl-10-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-ethyl-3-oxo-5-(tetrahydropyran-2-yloxy)-undec-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1a, the solution of 4.02 g (6.58 mmol) of thecompound that is presented according to Example 1ak is reacted, andafter working-up and purification, 4.26 g (6.13 mmol, 93%) of the titlecompound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.67-1.97 (47H), 3.02+3.12 (1H), 3.38 (1H), 3.48-4.04(5H), 4.18+4.26 (1H), 4.42+4.50 (1H), 7.30-7.46 (6H), 7.61-7.72 (4H)ppm.

EXAMPLE 1am(4S(4R,5S,6S,10RS))-4-(2,6-Dimethyl-4-ethyl-10-hydroxy-3-oxo-5-(tetrahydropyran-2-yloxy)-undec-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1i, the solution of 4.26 g (6.13 mmol) of thecompound that is presented according to Example 1al is reacted, andafter working-up and purification, 2.38 g (5.21 mmol, 85%) of the titlecompound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.78+0.84 (3H), 0.92-1.10 (6H), 1.13-1.98 (29H), 2.43(1H), 3.06+3.18 (1H), 3.42 (1H), 3.60-4.04 (5H), 4.21+4.28 (1H),4.42+4.54 (1H) ppm.

EXAMPLE 1an(4S(4R,5S,6S))-4-(3,10-Dioxo-2,6-dimethyl-4-ethyl-5-(tetrahydropyran-2-yloxy)-undec-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1m, the solution of 2.49 g (5.45 mmol) of thecompound that is presented according to Example 1am is reacted, andafter working-up and purification, 2.24 g (4.93 mmol, 90%) of the titlecompound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.78+0.86 (3H), 0.90-1.37 (15H), 1.37-1.95 (15H), 2.13(3H), 2.42 (2H), 3.07+3.18 (1H), 3.42 (1H), 3.60-4.04 (4H), 4.22+4.27(1H), 4.41+4.53 (1H) ppm.

EXAMPLE 1ao(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-ethyl-15-(2-methyl-4-thiazolyl)-3-oxo-5-(tetrahydropyran-2-yloxy)-2,6,10,14-tetramethyl-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane

The suspension of 4.92 g (5.97 mmol) of the compound(5E,3S)-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-methyl-5-(2-methyl-thiazol-4-yl)-pent-4-en-1-yl]-triphenylphosphoniumiodide, presented analogously to Example 1ai, in 14 ml of anhydroustetrahydrofuran is mixed at 0° C. under an atmosphere of dry argon with5.96 ml of a 1 M solution of sodium-bis-(trimethylsilyl)-amide intetrahydrofuran and allowed to heat to 23° C. The solution of 877 mg(1.93 mmol) of the compound, presented according to Example 1an, in 14ml of tetrahydrofuran is added in drops to the red solution, allowed tostir for 2 hours, poured onto saturated ammonium chloride solution andextracted several times with ethyl acetate. The combined organicextracts are dried on sodium sulfate and concentrated by evaporation ina vacuum. After column chromatography on silica gel with a gradientsystem that consists of n-hexane and ethyl acetate, in addition to 29%starting material, 732 mg (0.98 mmol, 51%) of the title compound isobtained.

¹H-NMR (CDCl₃): δ=0.01 (3H), 0.05 (3H), 0.79 (3H), 0.81-1.02 (6H), 0.90(9H), 1.04-1.38 (11H), 1.38-2.08 (19H), 1.60 (3H), 2.01 (3H), 2.16-2.34(2H), 2.72 (3H), 3.06+3.17 (1H), 3.42 (1H), 3.68 (1H), 3.80-4.03 (3H),4.03-4.32 (2H), 4.46+4.54 (1H), 5.13 (1H), 6.45 (1H), 6.92 (1H) ppm.

EXAMPLE 1ap(3S,6R,7S,8S,12E/Z,15S,16E)-6-Ethyl-17-(2-methyl-4-thiazolyl)-5-oxo-4,4,8,12,16-pentamethyl-heptadeca-12,16-diene-1,3,7,15-tetraol(A) and(3S,6R,7S,8S,12E/Z,15S,16E)-15-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-6-ethyl-17-(2-methyl-4-thiazolyl)-5-oxo-4,4,8,12,16-pentamethyl-heptadeca-12,16-diene-1,3,7-triol(B)

Analogously to Example 1f, the solution of 732 mg (0.98 mmol) of thecompound that is presented according to Example 1ao is reacted, andafter working-up and purification, 98 mg (0.19 mmol, 20%) of titlecompound A and 380 mg (0.61 mmol, 62%) of title compound B are isolatedin each case as a colorless oil.

¹H-NMR (CDCl₃) of A: δ=0.79-0.95 (6H), 0.98-1.19 (4H), 1.21-1.86 (15H),1.92-2.17 (5H), 2.33 (2H), 2.74 (3H), 2.87-3.23 (3H), 3.31-3.50 (1H),3.65-3.92 (3H), 4.05-4.20 (2H), 5.10-5.25 (1H), 6.53 (1H), 6.96 (1H)ppm.

¹H-NMR (CDCl₃) of B: δ=0.01+0.05 (6H), 0.80-0.96 (15H), 1.01-1.17 (4H),1.20-1.68 (4H), 1.68-1.90 (10H), 1.90-2.16 (5H), 2.25 (2H), 2.73+2.77(3H), 2.91 (1H), 3.19 (1H), 3.42 (1H), 3.61 (1H), 3.79-3.93 (3H),3.99-4.19 (2H), 5.10+5.20 (1H), 6.42 (1H), 6.94 (1H) ppm.

EXAMPLE 1aq(3S,6R,7S,8S,12E/Z,15S,16E)-6-Ethyl-17-(2-methyl-4-thiazolyl)-4,4,8,12,16-pentamethyl-1,3,7,15-tetrakis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-heptadeca-12,16-dien-5-one

The solution of 520 mg (about 0.86 mmol) of a mixture of compounds A andB, presented according to Example 1ap, in 25 ml of anhydrousdichloromethane is cooled under an atmosphere of dry argon to −78° C.,mixed with 2.6 ml of 2,6-lutidine and 2.57 ml oftrifluoromethanesulfonic acid-tert-butyldimethylsilyl ester and stirredfor 16 hours. It is poured into saturated sodium bicarbonate solutionand extracted several times with dichloromethane. The combined organicextracts are dried on sodium sulfate and concentrated by evaporation ina vacuum. After column chromatography on silica gel with a gradientsystem that consists of n-hexane and ethyl acetate, 1.14 g (max. 0.86mmol, max. 100%) of the title compound, which also contains silanol, isisolated.

¹H-NMR (CDCl₃) of an analytically purified sample: ¹H-NMR (CDCl₃)δ=−0.04-0.11 (24H), 0.78-0.96 (42H), 1.13 (3H), 1.20 (3H), 1.02-1.65(6H), 1.58+1.68 (3H), 1.72 (1H), 1.88-2.07 (2H), 2.00 (3H), 2.23 (2H),2.71 (3H), 3.01 (1H), 3.52-3.73 (2H), 3.82 (1H), 3.91 (1H), 4.09 (1H),5.13 (1H), 6.45 (1H), 6.91 (1H) ppm.

EXAMPLE 1ar(3S,6R,7S,8S,12E/Z,15S,16E)-3,7,15-6-Ethyl-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-1-hydroxy-17-(2-methyl-4-thiazolyl)-4,4,8,12,16-pentamethyl-heptadeca-12,16-dien-5-one

The solution of 1.14 g (max. 0.86 mmol) of the compound, presentedaccording to Example 1aq, in a mixture of 8 ml of dichloromethane and 8ml of methanol is mixed at 0° C. under an atmosphere of dry argon with204 mg of camphor-10-sulfonic acid, allowed to heat to 23° C. andstirred for 1.5 more hours. It is mixed with triethylamine, poured intoa saturated sodium bicarbonate solution and extracted several times withdichloromethane. The combined organic extracts are dried on sodiumsulfate and concentrated by evaporation in a vacuum. After columnchromatography on fine silica gel with a gradient system that consistsof n-hexane and ethyl acetate, 618 mg (0.78 mmol, 90%) of the titlecompound is isolated.

¹H-NMR (CDCl₃): δ=−0.02-0.13 (18H), 0.77-0.98 (33H), 1.01-1.80 (10H),1.08 (3H), 1.19 (3H), 1.55+1.66 (3H), 1.74-2.05 (2H), 2.00 (3H), 2.25(2H), 2.70 (3H), 3.00 (1H), 3.68 (2H), 3.85 (1H), 4.08 (2H), 5.14 (1H),6.44 (1H), 6.90 (1H) ppm.

EXAMPLE 1as(3S,6R,7S,8S,12E/Z,15S,16E)-6-Ethyl-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-methyl-4-thiazolyl)-5-oxo-heptadeca-12,16-dienal

Analogously to Example 1k, 510 mg (0.64 mmol) of the compound that ispresented according to Example 1ar is reacted, and after working-up, 545mg (max. 0.64 mmol) of the title compound is isolated as a crudeproduct, which is further reacted without purification.

EXAMPLE 1at(3S,6R,7S,8S,12E/Z,15S,16E)-6-Ethyl-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-methyl-4-thiazolyl)-5-oxo-heptadeca-12,16-dienoicacid

The solution of 545 mg (max. 0.64 mmol) of the compound, presentedaccording to Example 1as, in 15 ml of acetone is cooled to −30° C.,mixed with 460 μl of a standardized, 8N chromosulfuric acid solution andstirred for 1 hour. It is poured into a mixture of water and diethylether, the organic phase is washed with saturated sodium chloridesolution and dried on sodium sulfate. After filtration and removal ofthe solvent, 410 mg (0.47 mmol, 74% relative to the educt in Example1as) of the title compounds, which can be chromatographically separated,is isolated as a pale yellow oil.

¹H-NMR (CDCl₃) of the Z-isomer: δ=−0.02-0.15 (18H), 0.80-0.95 (33H),1.03-2.28 (12H), 1.17 (3H), 1.18 (3H), 1.69 (3H), 1.96 (3H), 2.35 (1H),2.54 (1H), 2.71 (3H), 3.03 (1H), 3.81 (1H), 4.16 (1H), 4.41 (1H), 5.20(1H), 6.53 (1H), 6.94 (1H) ppm.

¹H-NMR (CDCl₃) of the E-isomer: δ=−0.03-0.16 (18H), 0.79-0.95 (33H),0.99-2.06 (10H), 1.17 (3H), 1.19 (3H), 1.57 (3H), 1.97 (3H), 2.26 (2H),2.32 (1H), 2.61 (1H), 2.70 (3H), 3.09 (1H), 3.85 (1H), 4.09 (1H), 4.36(1H), 5.12 (1H), 6.48 (1H), 6.94 (1H) ppm.

EXAMPLE 1au(3S,6R,7S,8S,12E/Z,15S,16E)-3,7-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-15-hydroxy-6-ethyl-17-(2-methyl-4-thiazolyl)-5-oxo-4,4,8,12,16-pentamethyl-heptadeca-12,16-dienoicAcid

Variant I:

The solution of 310 mg (0.36 mmol) of the acid, presented according toExample 1at, in 30 ml of anhydrous tetrahydrofuran, is mixed under anatmosphere of dry argon with 500 μl of a hydrogen fluoride-pyridinecomplex and 7.1 ml of a 1.1 M solution of tetrabutylammonium fluoride intetrahydrofuran, and it is stirred for 3 days at 50° C. It is pouredinto a saturated ammonium chloride solution, extracted several timeswith ethyl acetate, the combined organic extracts are washed withsaturated sodium chloride solution and dried on sodium sulfate. Afterfiltration and removal of the solvent, the residue is purified bychromatography on about 200 ml of fine silica gel with a gradient systemthat consists of dichloromethane and methanol. 125 mg (max. 0.24 mmol,max. 66%), which also contains tetrabutylammonium salts, is isolated.

Variant II:

Analogously to Example 1t, 32 mg (37 μmol) of the acid that is presentedaccording to Example 1at is reacted, and after working-up andpurification, 16 mg (31 μmol, 83%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃) of the Z-isomer: δ=0.01-0.14 (12H), 0.80-0.99 (24H),1.02-1.67 (7H), 1.18 (3H), 1.19 (3H), 1.70 (1H), 1.73 (3H), 1.97 (1H),2.01 (3H), 2.14 (1H), 2.27-2.40 (3H), 2.53 (1H), 2.71 (3H), 2.81 (1H),3.01 (1H), 3.82 (1H), 4.17 (1H), 4.48 (1H), 5.19 (1H), 6.69 (1H), 6.95(1H) ppm.

¹H-NMR (CDCl₃) of the E-isomer: δ=−0.02-0.11 (12H), 0.73-0.95 (24H),1.00-1.63 (7H), 1.12 (3H), 1.17 (3H), 1.60 (3H), 1.71 (1H), 1.89-2.06(2H), 2.00 (3H), 2.22-2.39 (3H), 2.53 (1H), 2.69 (3H), 2.79 (1H), 3.02(1H), 3.79 (1H), 4.15 (1H), 4.34 (1H), 5.15 (1H), 6.56 (1H), 6.92 (1H)ppm.

EXAMPLE 1aw(4S,7R,8S,9S,13E/Z,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

The solution of 55 mg (73 μmol) of the compound, presented according toExample 1au, in 0.8 ml of anhydrous tetrahydrofuran is mixed with 46 μlof triethylamine and 44 μl of 2,4,6-trichlorobenzoyl chloride under anatmosphere of dry argon, and it is stirred for 20 minutes. It is dilutedwith 20 ml of tetrahydrofuran, mixed with 68 mg of4-dimethylaminopyridine and stirred for 30 minutes at 23° C. It isconcentrated by evaporation, taken up in a little dichloromethane andpurified by chromatography on 100 ml of fine silica gel with a gradientsystem that consists of n-hexane and ethyl acetate. 49 mg (65 μmol, 89%)of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃) of the Z-isomer: δ=−0.12 (3H), 0.08 (3H), 0.10 (3H), 0.13(3H), 0.73 (3H), 0.79-1.78 (7H), 0.85 (9H), 0.93 (9H), 0.99 (3H), 1.10(3H), 1.18 (3H), 1.67 (3H), 1.88 (1H), 2.05 (1H), 2.09 (3H), 2.45 (1H),2.54-2.74 (2H), 2.69 (3H), 2.77 (1H), 3.08 (1H), 4.00 (2H), 4.56 (1H),5.16 (1H), 6.56 (1H), 6.95 (1H) ppm.

¹H-NMR (CDCl₃) of the E-isomer: δ=0.02-0.16 (12H), 0.78-1.00 (24H), 1.09(3H), 1.14-1.93 (8H), 1.20 (3H), 1.59 (3H), 2.09-2.21 (1H), 2.13 (3H),2.39 (1H), 2.43-2.64 (3H), 2.70 (3H), 2.98 (1H), 3.95 (1H), 4.40 (1H),5.21 (1H), 5.29 (1H), 6.51 (1H), 6.92 (1H) ppm.

EXAMPLE 1(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione(A) and(4S,7R,8S,9S,13E,16S(E))-4,8-dihydroxy-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione(B)

The solution of 48 mg (64 μmol) of the compound, presented according toExample 1aw, in 3 ml of anhydrous dichloromethane, is mixed at −20° C.under an atmosphere of dry argon with 220 μl of an approximately 20%trifluoroacetic acid, and it is stirred for 1 hour. It is poured into asaturated sodium bicarbonate solution, extracted with dichloromethane,and the organic phase is dried on sodium sulfate. After filtration andremoval of the solvent, the residue is purified by repeatedchromatography on analytical thin-layer plates. As a mobile solvent, amixture of n-hexane and ethyl acetate is used; as an eluant, ethylacetate is used. 13 mg (25 μmol, 39%) of title compound A and 12 mg (23μmol, 36%) of title compound B are isolated in each case as a colorlessoil.

¹H-NMR (CDCl₃) of A: δ=0.89 (3H), 1.04 (3H), 1.09 (3H), 1.19-1.94 (8H),1.33 (3H), 1.70 (3H), 2.07 (3H), 2.15-2.33 (2H), 2.38 (1H), 2.44-2.74(3H), 2.70 (3H), 3.23 (1H), 3.62 (1H), 3.72 (1H), 4.24 (1H), 5.12 (1H),5.22 (1H), 6.57 (1H), 6.95 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.84 (3H), 1.01 (6H), 1.29 (3H), 1.38-2.00 (8H),1.61 (3H), 2.07 (3H), 2.20 (1H), 2.22-2.50 (3H), 2.58 (1H), 2.70 (3H),3.37 (1H), 3.73 (1H), 4.02 (1H), 4.12 (1H), 4.41 (1H), 5.05 (1H), 5.38(1H), 6.57 (1H), 6.99 (1H) ppm.

EXAMPLE 2(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

The solution of 10 mg (19 μmol) of compound A, presented according toExample 1, in 1 ml of dichloromethane is mixed under an atmosphere ofdry argon at −10° C. with 10 mg of an approximately 80%meta-chloroperbenzoic acid, and it is stirred for 4 hours at 0° C. It ispoured into a saturated sodium bicarbonate solution, extracted withdichloromethane, and the organic phase is dried on sodium sulfate. Afterfiltration and removal of the solvent, the residue is purified byrepeated chromatography on analytic thin-layer plates. As a mobilesolvent, mixtures of n-hexane and ethyl acetate as well asdichloromethane and methanol are used; as an eluant, ethyl acetate isused. 4.5 mg (8.4 μmol, 44%) of title compound A and 1 mg (1.9 μmol,10%) of title compound B are used as colorless foams.

¹H-NMR (CDCl₃) of A: δ=0.86 (3H), 1.00 (3H), 1.05 (3H), 1.28 (3H),1.33-2.12 (10H), 1.38 (3H), 2.11 (3H), 2.41 (1H), 2.57 (1H), 2.70 (3H),2.77-2.85 (2H), 3.38 (1H), 3.49 (1H), 3.67 (1H), 4.27 (1H), 4.56 (1H),5.46 (1H), 6.57 (1H), 6.97 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.85 (3H), 0.95 (3H), 1.03 (3H), 1.22-1.73 (10H),1.30 (3H), 1.38 (3H), 2.08 (1H), 2.61 (3H), 2.41-2.59 (2H), 2.71 (3H),2.91 (1H), 2.99 (1H), 3.24 (1H), 3.43 (1H), 3.96 (1H), 4.30 (1H), 5.60(1H), 6.60 (1H), 6.98 (1H) ppm.

EXAMPLE 3(1R,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1S,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclor[4.1.0]heptadecane-5,9-dione(B)

Analogously to Example 2, 10 mg (19 μmol) of compound B that ispresented according to Example 1 is reacted, and after working-up andpurification, 6 mg (11 μmol, 59%) of a mixture of the two titlecompounds is isolated as a colorless foam.

¹H-NMR (CDCl₃) of A or B: δ=0.86 (3H), 0.96 (3H), 1.03 (3H), 1.06-2.08(1H), 1.28 (3H), 1.38 (3H), 2.09 (3H), 2.46-2.59 (2H), 2.70 (3H), 2.87(1H), 3.02 (1H), 3.33 (1H), 3.79 (1H), 4.22 (1H), 4.34 (1H), 5.49 (1H),6.65 (1H), 7.00 (1H) ppm.

¹H-NMR (CDCl₃) of B or A: δ=0.86 (3H), 0.96 (3H), 1.09 (3H), 1.21-1.94(9H), 1.25 (3H), 1.37 (3H), 2.03 (2H), 2.09 (3H), 2.50-2.61 (2H), 2.71(3H), 2.87 (1H), 2.94 (1H), 3.28 (1H), 3.67 (1H), 3.72 (1H), 4.27 (1H),5.46 (1H), 6.59 (1H), 6.97 (1H) ppm.

EXAMPLE 4(4S,7S,8R,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione(A) and(4S,7S,8R,9S,13E,16S(E))-4,8-dihydroxy-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione(B)

Diastereomeric compound B that is produced according to Example 1ak isreacted analogously to Examples 1al to 1aw and 1 to title compounds Aand B.

EXAMPLE 5(1S,3S(E),7S,10S,11R,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(E),7S,10S,11R,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 2, Compound A that is produced according toExample 4 is reacted to separable title compounds A and B.

EXAMPLE 6(1S,3S(E),7S,10,S,11R,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dioneand(1R,3S(E),7S,10S,11R,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

Compound B that is produced according to Example 4 is reactedanalogously to Example 2 in a mixture of title compounds.

EXAMPLE 7(4S,7R,8S,9S,13(Z),16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-((3-pyridyl)ethenyl)-1-oxa-cyclohexadec-13-ene-2,6-dione(A) and(4S,7R,8S,9S,13E,16S(E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((3-pyridyl)ethenyl)-1-oxa-cyclohexadec-13-ene-2,6-dione(B) EXAMPLE 7a(Z,3S)-1-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(3-pyridyl)-pent-4-ene(A) and(E,3S)-1-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(3-pyridyl)-pent-4-ene(B)

Analogously to Example 1af, 4.8 g (10.2 mmol) of the compound that ispresented according to Example 1ae is reacted with use ofdiethyl(3-pyridyl)methanephosphonate, and after working-up andpurification, 448 mg (0.82 mmol, 8%) of title compound A and 3.5 g (6.41mmol, 63%) of title compound B are isolated in each case as a colorlessoil.

¹H-NMR (CDCl₃) of A: δ=−0.06 (6H), 0.81 (9H), 1.01 (9H), 1.75 (1H), 1.97(4H), 3.48 (2H), 4.83 (1H), 6.11 (1H), 6.97 (1H), 7.11-7.30 (5H),7.30-7.39 (2H), 7.39-7.50 (4H), 8.08 (1H), 8.33 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=−0.01 (6H), 0.85 (9H), 1.11 (9H), 1.78 (3H), 1.83(1H), 1.97 (1H), 3.58 (2H), 4.42 (1H), 6.03 (1H), 7.21 (1H), 7.28-7.50(7H), 7.62-7.75 (4H), 8.29 (1H), 8.41 (1H) ppm.

EXAMPLE 7b(E,3S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(3-pyridyl)-pent-4-en-1-ol

Analogously to Example 1ag, 3.5 g (6.41 mmol) of the compound that isproduced under Example 7aB is reacted with a 65:35:10 mixture of glacialacetic acid/water/tetrahydrofuran. After purification, 2.1 g (4.86 mmol,76%) is obtained.

¹H-NMR (CDCl₃): δ=1.12 (9H), 1.75 (3H), 1.88 (2H), 3.65 (2H), 4.45 (1H),6.25 (1H), 7.21 (1H), 7.28-7.50 (7H), 7.60-7.75 (4H), 8.30 (1H), 8.44(1H) ppm.

EXAMPLE 7c(E,3S)-1-Iodo-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(3-pyridyl)-pent-4-ene

Analogously to Example 1ah, 1.98 g (3.66 mmol, 75%) of the titlecompound is obtained from 2.1 g (4.86 mmol) of the compound that isdescribed under Example 7b.

¹H-NMR (CDCl₃): δ=1.11 (9H), 1.78 (3H), 2.17 (2H), 3.03 (2H), 4.29 (1H),6.19 (1H), 7.22 (1H), 7.30-7.50 (7H), 7.63-7.75 (4H), 8.32 (1H), 8.44(1H) ppm.

EXAMPLE 7d(5E,3S)-[3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(3-pyridyl)-pent-4-en-1-yl]-triphgenylphosphoniumIodide

Analogously to Example 1ai, 2.35 g (2.93 mmol, 80%) of the titlecompound is obtained from 1.98 g (3.66 mmol) of the compound that isdescribed under Example 7c.

¹H-NMR (CDCl₃): δ=1.08 (9H), 1.80 (3H), 3.27 (1H), 3.56 (1H), 4.66 (1H),6.52 (1H), 7.25-7.90 (27H), 8.35 (1H), 8.46 (1H) ppm.

EXAMPLE 7e(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-2,4,6,10,14-pentamethyl-15-(3-pyridyl)-3-oxo-5-(tetrahydropyran-2-yloxy)-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1ao, 800 mg (1.76 mmol) of the compound(4S(4R,5S,6S))-4-(3,10-dioxo-2,4,6-trimethyl-5-(tetrahydropyran-2-yloxy)-undec-2-yl)-2,2-dimethyl-[1,3]dioxanethat is produced analogously to Examples 1l (reaction withethylmagnesium bromide) to 1an is reacted with 4.24 g (5.28 mmol) of thecompound that is described under Example 7d, and 5.44 ml of a 1 Msolution of sodium-bis-(trimethylsilyl)-amide in tetrahydrofuran. 684 mg(0.79 mmol, 45%) of the title compound is obtained.

¹H-NMR (CDCl₃): δ=0.86-0.98 (3H), 0.98-1.94 (45H), 2.20-2.42 (2H), 3.22(1H), 3.42 (1H), 3.58-4.02 (4H), 4.08-4.22 (2H), 4.46+4.52 (1H), 5.00(1H), 6.03 (1H), 7.19 (1H), 7.24-7.47 (7H), 7.60-7.73 (4H), 8.28+8.40(2H) ppm.

EXAMPLE 7f(3S,6R,7S,8S,12E/Z,15S,16E)-15-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(3-pyridyl)-5-oxo-heptadeca-12,16-diene-1,3,7-triol

Analogously to Example 1ap, 542 mg (0.73 mmol, 92%) of the titlecompound is obtained from 684 mg (0.79 mmol) of the compound that isdescribed under Example 7e.

EXAMPLE 7g(3S,6R,7S,8S,12E/Z,15S,16E)-15-[[(1,1-Dimethylethyl)-diphenylsilyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(3-pyridyl)-1,3,7-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-heptadeca-12,16-dien-5-one

Analogously to Example 1aq, 995 mg (max. 0.73 mmol, max. 100%) of thetitle compound, which is contaminated with silanol, is obtained from 542mg (0.73 mmol) of the compound that is described under Example 7f.

EXAMPLE 7h(3S,6R,7S,8S,12E/Z,15S,16E)-3,7-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-15-[[(1,1-dimethylethyl)-diphenylsilyl]oxy]-1-hydroxy-4,4,6,8,12,16-hexamethyl-17-(3-pyridyl)-heptadeca-12,16-dien-5-one

Analogously to Example 1ar, 604 mg (0.62 mmol, 85%) of the titlecompound is obtained from 995 mg (max. 0.73 mmol) of the compound thatis described under Example 7g.

EXAMPLE 7i(3S,6R,7S,8S,12E/Z,15S,16E)-3,7-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-15-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(3-pyridyl)-5-oxo-heptadeca-12,16-dienoicacid

Analogously to Examples 1as and 1at, 550 mg (0.56 mmol, 90%) of thetitle compound is obtained from 604 mg (0.62 mmol) of the compound thatis described under Example 7h.

EXAMPLE 7k(3S,6R,7S,8S,12E/Z,15S,16E)-4,4,6,8,12,16-Hexamethyl-17-(3-pyridyl)-5-oxo-3,7,15-trihydroxy-heptadeca-12,16-dienoicacid

Analogously to Example 1au, 269 mg (0.49 mmol, 88%) of the titlecompound is obtained from 550 mg (0.56 mmol) of the compound that isdescribed under Example 7i.

EXAMPLE 7l(3s,6R,8s,12E/Z,15S,16E)-3,7-Bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-15-hydroxy-17-(3-pyridyl)-5-oxy-heptadeca-12,16-dienoicacid

Analogously to Example 1av, 127 mg (0.17 mmol, 35%) of the titlecompound is obtained from 269 mg (0.49 mmol) of the compound that isdescribed under Example 7k.

Alternative Production of 7l over 7n to 7r:

EXAMPLE 7n(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-Hydroxy-2,4,6,10,14-pentamethyl-15-(3-pyridinyl)-3-oxo-5-(tetrahydropyran-2-yloxy)-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1i, 486 mg (0.81 mmol, 95%) of the title compoundis obtained from 710 mg (0.85 mmol) of the compound that is describedunder 7e.

¹H-NMR (CDCl₃): δ=0.90-1.00 (3H), 1.05-1.90 (36H), 2.38 (2H), 3.27 (1H),3.46 (1H), 3.63+3.80-4.00 (4H), 4.10-4.20 (2H) 4.46+4.55 (1H), 5.15(1H), 6.49 (1H), 7.24 (1H), 7.57 (1H), 8.47 (1H), 8.54 (1H) ppm.

EXAMPLE 7o(3S,6R,7S,8S,12E/Z,15S,16E)-4,4,6,8,12,16-Hexamethyl-17-(3-pyridyl)-1,3,7,15-tetra-hydroxy-heptadeca-12,16-dien-5-one

Analogously to Example 1f, 335 mg (0.71 mmol, 87%) of the title compoundis obtained from 486 mg (0.81 mmol) of the compound that is describedunder 7n.

¹H-NMR (CDCl₃):δ=0.82+0.86 (3H), 1.08+1.10 (3H), 1.13 (3H), 1.22 (3H),1.68+1.72 (3H), 1.90 (3H), 2.40 (2H), 3.30 (1H), 3.35-3.48 (2H),3.85-3.96 (2H), 4.17 (1H), 4.20 (1H), 5.05 (1H), 6.50 (1H), 7.25 (1H),7.61 (1H), 8.45 (1H), 8.53 (1H) ppm.

EXAMPLE 7p(3S,6R,7S,8S,12E/Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-1-hydroxy-4,4,6,8,12,16-hexamethyl-17-(3-pyridyl)-heptadeca-12,16-dien-5-one

Analogously to Example 1aq, 730 mg (max. 0.71 mmol, max. 100%) of thetitle compound, which is contaminated with silanol, is obtained from 335mg (0.71 mmol) of the compound that is described under 7o.

¹H-NMR (CDCl₃): δ=0.05-1.16 (24H), 0.85-0.97 (39H), 1.02+1.04+1.07 (6H),1.22 (3H), 1.60 (3H), 1.70+1.83 (3H), 2.29 (1H), 3.13 (1H), 3.05-3.80(2H), 3.76 (1H), 3.89 (1H), 4.11 (1H), 5.13 (1H), 6.46 (1H), 7.23 (1H),7.54 (1H), 8.42 (1H), 8.50 (1H) ppm.

EXAMPLE 7q(3S,6R,7S,8S,12E/Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-1-hydroxy-4,4,6,8,12,16-hexamethyl-17-(3-pyridyl)-heptadeca-12,16-dien-5-one

Analogously to Example 1ar, 441 mg (0.54 mmol, 76%) of the titlecompound is obtained from 730 mg (max. 0.71 mmol) of the compound thatis described under 7p.

¹H-NMR (CDCl₃): δ=0.05-0.18 (18H), 0.90-1.10 (30H), 1.11 (6H), 1.25(3H), 1.62+1.70 (3H), 1.82 (3H), 2.38 (1H), 3.13 (1H), 3.63 (2H), 3.81(1H), 4.05-4.15 (2H), 5.17 (1H), 6.38 (1H), 7.22 (1H), 7.53 (1H), 8.45(1H), 8.52 (1H) ppm.

EXAMPLE 7r(3S,6R,7S,8S,12E/Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(3-pyridyl)-5-oxo-heptadeca-12,16-dienoicAcid

Analogously to Examples 1as and 1at, 316 mg (0.38 mmol, 70%) of thetitle compound is obtained from 441 mg (0.38 mmol) of the compound thatis described under 7q.

¹H-NMR (CDCl₃): δ=0.00-0.18 (18H), 0.90-1.00 (30H), 1.12 (3H), 1.13+1.14(3H), 1.19 (3H), 1.62+1.70 (3H), 1.79+1.80 (3H), 3.18 (1H), 3.75+3.80(1H), 4.19 (1H), 4.44+4.48 (1H), 5.12+5.14 (1H), 6.32+6.35 (1H), 7.30(1H), 7.60+7.62 (1H), 8.38+8.40 (1H), 8.58 ppm.

EXAMPLE 7l(3S,6R,8S,12E/Z,15S,16E)-3,7-Bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-15-hydroxy-17-(3-pyridyl)-5-oxy-heptadeca-12,16-dienoicAcid

Analogously to Example 1i, 295 mg (max. 0.38 mmol, max. 100%) of thetitle compound is obtained from 316 mg (0.38 mmol) of the compound thatis described under 7r.

¹H-NMR (CDCl₃): δ=0.00-0.18 (12H), 0.88-1.00 (21H), 1.10 (3H), 1.15(3H), 1.18 (3H), 1.63+1.70 (3H), 1.84+1.86 (3H), 2.30-2.50 (3H), 3.10(1H), 3.75+3.78 (1H), 4.20+4.25 (1H), 4.45 (1H), 5.14 (1H), 6.49 (1H),7.33 (1H), 7.68 (1H), 8.41 (1H), 8.60 (1H) ppm.

EXAMPLE 7m(4S,7R,8S,13E/Z,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-16-((3-prydiyl)ethenyl)1-oxa-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1aw, 104 mg (0.14 mmol, 85%) of the titlecompound is obtained from 127 mg (0.17 mmol) of the compound that isdescribed under Example 7l.

¹H-NMR (CDCl₃): δ=−0.05-0.13 (12H), 0.82-1.00 (21H), 1.12 (3H), 1.15(3H), 1.23 (3H), 1.60+1.69 (3H), 1.90+1.92 (3H), 2.40-2.60 (4H), 3.02(1H), 3.88+3.90 (1H), 4.10 (1H), 4.48 (1H), 5.07+5.14 (1H), 5.18+5.25(1H), 6.47+6.50 (1H), 7.25 (1H), 7.55+7.60 (1H), 8.45 (1H), 8.50+8.53(1H) ppm.

EXAMPLE 7(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-((3-pyridyl)ethenyl)-1-oxa-cyclohexadec-13-ene-2,6-dione(A) and(4S,7R,8S,9S,13E,16S(E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((3-pyridyl)ethenyl)-1-oxa-cyclohexadec-13-ene-2,6-dione(B)

Analogously to Example 1, 24 mg (48 μmol, 34%) of title compound A and25 mg (50 μmol, 36%) of title compound B are obtained from 104 mg (0.14mmol) of the compound that is described under Example 7m.

¹H-NMR (CDCl₃) Compound A: δ=1.03 (3H), 1.10 (3H), 1.21 (3H), 1.32 (3H),1.62 (3H), 1.92 (3H), 2.18-2.80 (6H), 3.14 (1H), 3.73 (1H), 4.16 (1H),5.17 (1H), 5.29 (1H), 6.51 (1H), 7.25 (1H) 7.58 (1H), 8.47 (1H), 8.53(1H) ppm.

Compound A: δ=1.00 (3H), 1.05 (3H), 1.16 (3H), 1.30 (3H), 1.63 (3H),1.91 (3H), 2.18-2.65 (6H), 3.22 (1H), 3.65 (1H), 4.20 (1H), 5.11 (1H),5.43 (1H), 6.49 (1H), 7.27 (1H), 7.59 (1H), 8.49 (1H), 8.52 (1H) ppm.

EXAMPLE 8(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-((3-pyridyl)ethenyl)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1S,3S(E),7S,11R,11S,12S,16S)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-((3-pyridyl)ethenyl)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B) and(1S,3S(E),7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-((3-N-oxypyridyl)ethenyl)-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(C) and(1S,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-((3-N-oxypyridyl)ethenyl)-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(D)

Analogously to Example 2, 7.4 mg (14 μmol, 46%) of title compound A, 1.6mg (3 μmol, 10%) of title compound B, 2.4 mg of title compound C and 0.9mg (4.4 mmol, 15%) of title compound D (1.7 mg, 6%) are obtained from 15mg (30 μmol) of the compound that is described under Example 7.

¹H-NMR (CDCl₃): Compound C: δ=1.03 (3H), 1.10 (3H), 1.17 (3H), 1.28(3H), 1.22 (3H), 1.91 (3H), 2.40-2.63 (3H), 2.79 (1H), 3.33 (1H), 3.68(1H), 3.77 (1H), 4.12 (3H), 5.46 (1H), 6.46 (1H), 7.18 (1H), 7.25 (1H),8.11 (1H), 8.18 (1H) ppm.

Compound D: δ=0.97 (3H), 1.10 (3H), 1.13 (3H), 1.28 (3H), 1.40 (3H),1.95 (3H), 2.50 (1H), 3.12 (1H), 3.34 (1H), 3.80 (1H), 4.08 (1H), 4.16(1H), 5.69 (1H), 6.47 (1H), 7.17 (1H), 7.26 (1H), 8.11 (1H), 8.18 (1H)ppm.

EXAMPLE 9(4S,7R,8S,9S,13(Z),16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-((4-pyridyl)ethenyl)-1-oxa-cyclohexadec-13-ene-2,6-dione(A) and(4S,7R,8S,9S,13E,16S(E))-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((4-pyridyl)ethenyl)-1-oxa-cyclohexadec-13-ene-2,6-dione(B) EXAMPLE 9a(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-2,4,6,10,14-pentamethyl-15-(4-pyridyl)-3-oxo-5-(tetrahydropyran-2-yloxy)-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 7e, 2.08 g (4.70 mmol) of the compound(4S(4R,5S,6S))-4-(3,10-dioxo-2,4,6-trimethyl-5-(tetrahydropyran-2-yloxy)-undec-2-yl)-2,2-dimethyl-[1,3]dioxanethat is produced analogously to Examples 1l (reaction withethylmagnesium bromide) to 1an is reacted with 11.4 g (14.2 mmol) of(5E,3S)-[3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(4-pyridyl)-pent-4-en-1-yl]-triphenylphosphoniumiodide, which has been produced analogously to Examples 7a to 7d usingdiethyl(4-pyridyl)methanephosphonate. After working-up and purification,2.10 g (2.5 mmol, 53%) of the title compound is isolated.

¹H-NMR (CDCl₃): δ=0.81-1.95 (49H), 2.20-2.42 (2H), 3.23 (1H), 3.42 (1H),3.58-4.02 (3H), 4.06-4.21 (2H), 4.46+4.52 (1H), 4.99 (1H), 6.03 (1H),6.94 (2H), 7.22-7.48 (6H), 7.59-7.73 (4H), 8.49 (2H) ppm.

EXAMPLE 9b(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-Hydroxy-2,4,6,10,14-pentamethyl-15-(4-pyridyl)-3-oxo-5-(tetrahydropyran-2-yloxy)-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1i, 550 mg (0.91 mmol, 98%) of the title compoundis obtained from 780 mg (0.93 mmol) of the compound that is describedunder Example 9a.

¹H-NMR (CDCl₃): δ=0.80-1.85 (33H), 1.91 (3H), 1.94-2.11 (5H), 2.36 (2H),3.27 (1H), 3.43 (1H), 3.61-4.01 (3H), 4.08-4.21 (2H), 4.46+4.54 (1H),5.16 (1H), 6.48 (1H), 7.18 (2H), 8.55 (2H) ppm.

EXAMPLE 9c(3S,6R,7S,8S,12E/Z,15S,16E)-4,4,6,8,12,16-Hexamethyl-17-(4-pyridyl)-1,3,7,15-tetra-hydroxy-heptadeca-12,16-dien-5-one

Analogously to Example 1f, 340 mg (0.71 mmmol, 71%) of the titlecompound is obtained from 600 mg (1.00 mmol) of the compound that isdescribed under Example 9b with use of p-toluenesulfonic acid.

¹H-NMR (CDCl₃): δ=0.82 (3H), 1.06 (3H), 1.12 (3H), 1.22 (3H), 1.73 (3H),0.90-1.83 (9H), 1.91 (3H), 1.95-2.13 (3H), 2.30-2.47 (2H), 3.19-3.35(2H), 3.42 (1H), 3.81-3.97 (2H), 4.04 (1H), 4.19 (1H), 5.18 (1H), 6.46(1H), 7.18 (2H), 8.52 (2H) ppm.

EXAMPLE 9d(3S,6R,7S,8S,12E/Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-1-hydroxy-4,4,6,8,12,16-hexamethyl-17-(4-pyridyl)-heptadeca-12,16-dien-5-one

Analogously to Example 1aq, 435 mg (0.47 mmol, 74%) of the titlecompound is obtained from 300 mg (0.63 mmol) of the compound that isdescribed under Example 9c.

¹H-NMR (CDCl₃): δ=−0.01-0.14 (24H), 0.82-0.97 (37H), 1.02 (3H), 1.04(3H), 1.21 (3H), 0.98-1.70 (12H), 1.87 (3H), 1.90-2.03 (2H), 2.25 (2H),3.13 (1H), 3.51-3.71 (2H), 3.76 (1H), 3.88 (1H), 4.03-4.14 (1H), 5.13(1H), 6.34 (1H), 7.13 (2H), 8.52 (2H) ppm.

EXAMPLE 9e(3S,6R,7S,8S,12E/Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-1-hydroxy-4,4,6,8,12,16-hexamethyl-17-(4-pyridyl)-heptadeca-12,16-dien-5-one

Analogously to Example 1ar, 339 mg (0.41 mmol, 94%) of the titlecompound is obtained from 410 mg (0.44 mmol) of the compound that isdescribed under Example 9d.

¹H-NMR (CDCl₃): δ=−0.01-0.14 (18H), 0.80-0.95 (31H), 0.97-1.70 (7H),1.06 (6H), 1.21 (3H), 1.59+1.69 (3H), 1.87 (3H), 1.90-2.06 (2H), 2.26(2H), 3.12 (1H), 3.65 (2H), 3.80 (1H), 4.09 (2H), 5.14 (1H), 6.36 (1H),7.13 (2H), 8.53 (2H) ppm.

EXAMPLE 9f(3S,6R,7S,8S,12E/Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(4-pyridyl)-5-oxo-heptadeca-12,16-dienoicAcid

Analogously to Examples 1as and 1at, 204 mg (0.25 mmol, 72%) of thetitle compound is obtained from 280 mg (0.34 mmol) of the compound thatis described under Example 9e.

¹H-NMR (CDCl₃): δ=0.00-0.14 (18H), 0.78-0.98 (30H), 1.06 (3H), 1.08(3H), 1.24 (3H), 1.05-1.55 (5H), 1.60+1.69 (3H), 1.87 (3H), 1.98 (2H),2.20-2.37 (3H), 2.10-3.10 (1H), 2.51 (1H), 3.14 (1H), 3.79 (1H), 4.11(1H), 4.40 (1H), 5.13 (1H), 6.36 (1H), 7.17 (2H), 8.53 (2H) ppm.

EXAMPLE 9g(3S,6R,8S,12E/Z,15S,16E)-3,7-Bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-15-hydroxy-17-(4-pyridyl)-5-oxy-heptadeca-12,16-dienoicAcid

Analogously to Example 1av, 132 mg (0.18 mmol, 77%) of the titlecompound is obtained from 198 mg (0.24 mmol) of the compound that isdescribed under Example 9f.

¹H-NMR (CDCl₃): δ=0.00-0.15 (12H), 0.85-1.00 (18H), 1.10-1.18 (6H),1.20-1.28 (6H), 1.62+1.73 (3H), 2.05 (1H), 2.20-2.50 (4H), 2.85 (1H),3.15 (1H), 3.79 (1H), 4.18 (1H), 4.42 (1H), 5.18 (1H), 6.50 (1H),7.15-7.25 (2H), 8.50-8.60 (2H) ppm.

EXAMPLE 9h(4S,7R,8S,13E/Z,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-16-((4-pyridyl)ethenyl)l-oxa-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1aw, 98 mg (0.14 mmol, 76%) of the title compoundis obtained from 130 mg (0.18 mmol) of the compound that is describedunder Example 9g.

EXAMPLE 9(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-((4-pyridyl)ethenyl)-1-oxa-cyclohexadec-13-ene-2,6-dione(A) and(4S,7R,8S,9S,13E,16S(E)))-4,8dihydroxy-5,5,7,9,13-pentamethyl-16-((4-pyridyl)ethenyl)-1-oxa-cyclohexadec-13-ene-2,6-dione(B)

Analogously to Example 1, 24 mg (49 μmol, 35%) of title compound A and21 mg (43 μmol, 31%) of title compound B are obtained from 98 mg (0.14mmol) of the compound that is described under Example 9h.

EXAMPLE 10(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-((4-pyridyl)ethenyl)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1S,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-((4-pyridyl)ethenyl)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 2, 11 mg (22 μmol, 59%) of title compound A isobtained from 18 mg (37 μmol) of compound A that is described underExample 9, or 9 mg (18 μmol, 58%) of title compound B is obtained from15 mg (31 μmol) of compound B.

EXAMPLE 11(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(3-N-oxido-2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

Analogously to Example 2, 10 mg (19 μmol) of compound A that ispresented according to Example 2 is reacted at 23° C., and afterworking-up and purification, 3.5 mg (6.5 μmol, 34%) of the titlecompound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.90 (3H), 1.03 (3H), 1.07 (3H), 1.10-2.03 (9H), 1.31(3H), 1.43 (3H), 2.03 (1H), 2.09 (3H), 2.19-2.26 (2H), 2.52 (1H), 2.61(3H), 2.68-2.81 (2H), 3.34 (1H), 3.65 (1H), 4.59 (1H), 5.39 (1H), 6.61(1H), 6.81 (1H), 7.08 (1H) ppm.

EXAMPLE 12(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-benzyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dioneEXAMPLE 12a(4S)-4-((3RS)-2-Methyl-3-hydroxy-5-phenyl-pent-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 11, 2.97 g (15.9 mmol) of the compound that ispresented according to Example 1k is reacted with use ofphenethylmagnesium bromide, and after working-up and purification, 3.27g (11.2 mmol, 70%) of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.72+0.88 (3H), 0.89+0.93 (3H), 1.33 (1H), 1.39+1.42(3H), 1.47+1.50 (3H), 1.58-1.93 (3H), 2.61 (1H), 3.00 (1H), 3.48-3.60(1H), 3.72-4.03 (4H), 7.13-7.35 (5H) ppm.

EXAMPLE 12b(4S)-4-(2-Methyl-3-oxo-5-phenyl-pent-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1m, 2.71 g (9.3 mmol) of the compound that ispresented according to Example 12a is reacted, and after working-up andpurification, 2.35 g (8.1 mmol, 87%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=1.03 (3H), 1.12 (3H), 1.28 (1H), 1.31 (3H), 1.38 (3H),1.60 (1H), 2.77-2.92 (4H), 3.83 (1H), 3.93 (1H), 4.02 (1H), 7.12-7.22(3H), 7.22-7.32 (2H) ppm.

EXAMPLE 12c(4S(4R,5S,6S,10RS))-4-(2,6-Dimethyl-10-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-benzyl-5-hydroxy-3-oxo-undec-2-yl)-2,2-dimethyl-[1,3]dioxane(A) and(4S(4S,5R,6S,10RS))-4-(2,6-dimethyl-10-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-benzyl-5-hydroxy-3-oxo-undec-2-yl)-2,2-dimethyl-[1,3]dioxane(B)

Analogously to Example 1ak, 2.34 g (8.06 mmol) of the compound that ispresented according to Example 12b is reacted, and after working-up andpurification, 2.91 g (4.32 mmol, 54%) of title compound A and 1.72 g(2.55 mmol, 32%) of title compound B are isolated in each case as acolorless oil.

¹H-NMR (CDCl₃) of A: δ=0.38 (3H), 0.83-1.82 (31H), 2.66-3.02 (3H), 3.47(1H), 3.58 (1H), 3.74-3.94 (4H), 7.05-7.28 (5H), 7.31-7.46 (6H),7.61-7.72 (4H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.78 (3H), 0.82-1.66 (21H), 0.98 (3H), 1.29 (3H),1.36 (3H), 2.78 (1H), 2.94 (1H), 3.05 (1H), 3.44 (1H), 3.54 (1H),3.72-3.91 (4H), 7.04-7.29 (5H), 7.31-7.48 (6H); 7.63-7.75 (5H) ppm.

EXAMPLE 12d(4S(4R,5S,6S,10RS))-4-(2,6-Dimethyl-10-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-benzyl-3-oxo-5-(tetrahydropyran-2-yloxy)-undec-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1a, 2.90 g (4.4 mmol) of compound A that ispresented according to Example 12c is reacted, and after working-up andpurification, 3.18 g (4.2 mmol, 95%) of the title compound is isolatedas a colorless oil.

EXAMPLE 12e(4S(4R,5S,6S,10RS))-4-(2,6-Dimethyl-4-benzyl-10-hydroxy-3-oxo-5-(tetrahydropyran-2-yloxy)-undec-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1i, 3.18 g (4.20 mmol) of the compound that ispresented according to Example 12d is reacted, and after working-up andpurification, 1.39 g (2.68 mmol, 64%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.28+0.47+0.49 (3H), 0.92-1.14 (7H), 1.14-1.95 (24H),2.79+2.99-3.13 (2H), 3.34-4.27 (8H), 4.45+4.56 (1H), 7.05-7.29 (5H) ppm.

EXAMPLE 12f(4S(4R,5S,6S))-4-(2,6-Dimethyl-4-benzyl-3,10-dioxo-5-(tetrahydropyran-2-yloxy)-undec-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1m, 1.39 g (2.68 mmol) of the compound that ispresented according to Example 12e is reacted, and after working-up andpurification, 1.18 g (2.28 mmol, 85%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.26+0.47 (3H), 0.96-1.11 (7H), 1.27+1.31 (3H),1.39+1.41 (3H), 1.20-1.90 (12H), 2.15 (3H), 2.45 (2H), 2.79+2.97-3.12(2H), 3.36-4.07 (6H), 4.15+4.21 (1H), 4.43+4.54 (1H), 7.08-7.28 (5H)ppm.

EXAMPLE 12g(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-benzyl-15-(2-methyl-4-thiazolyl)-3-oxo-5-(tetrahydropyran-2-yloxy)-2,6,10,14-tetramethyl-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1ao, 477 mg (923 μmol) of the compound that ispresented according to Example 12f is reacted with use of n-butyllithiumas a base, and after working-up and purification, 367 mg (393 μmol, 43%)of the title compound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.23+0.46 (3H), 0.92-1.10 (19H), 1.10-1.92 (22H), 1.99(3H), 2.13-2.40 (2H), 2.70 (3H), 2.80+2.94-3.14 (2H), 3.35-4.25 (6H),4.47+4.53 (1H), 4.98 (1H), 6.22 (1H), 6.77 (1H), 7.07-7.24 (5H),7.25-7.45 (6H), 7.60-7.73 (4H) ppm.

EXAMPLE 12h(4S(4R,5S,6S,10E/Z,13S,14E))-4-(4-Benzyl-13-hydroxy-15-(2-methyl-4-thiazolyl)-3-oxo-5-(tetrahydropyran-2-yloxy)-2,6,10,14-tetramethyl-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1i, 548 mg (586 μmol) of the compound that ispresented according to Example 12g is reacted, and after working-up andpurification, 330 mg (474 μmol, 81%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.25+0.46 (3H), 0.92-1.10 (6H), 1.10-1.90 (13H),1.28+1.32 (3H), 1.39+1.41 (3H), 1.68+1.74 (3H), 1.99-2.13 (2H), 2.06(3H), 2.36 (2H), 2.71 (3H), 2.81+3.00-3.14 (2H), 3.37-4.26 (9H),4.48+4.57 (1H), 5.20 (1H), 6.58 (1H), 6.94 (1H), 7.08-7.26 (5H) ppm.

EXAMPLE 12i3S,6R,7S,8S,12E/Z,15S,16E)-6-Benzyl-17-(2-methyl-4-thiazolyl)-5-oxo-4,4,8,12,16-pentamethyl-heptadeca-12,16-diene-1,3,7,15-tetraol

Analogously to Example 1f, 330 mg (474 μmol) of the compound that ispresented according to Example 12h is reacted, and after working-up andpurification, 224 mg (392 μmol, 83%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.40 (3H), 0.93-1.04 (6H), 1.08-1.87 (8H), 1.63+1.71(3H), 1.92-2.11 (5H), 2.33 (2H), 2.67-3.06 (3H), 2.72 (3H), 3.11 (1H),3.23-3.50 (2H), 3.54 (1H), 3.65-3.92 (3H), 4.13 (1H), 5.18 (1H), 6.53(1H), 6.94 (1H), 7.06-7.29 (5H) ppm.

EXAMPLE 12k(3S,6R,7S,8S,12E/Z,15S,16E)-6-Benzyl-17-(2-methyl-4-thiazolyl)-4,4,8,12,16-pentamethyl-1,3,7,15-tetrakis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-heptadeca-12,16-dien-5-one

Analogously to Example 1aq, 224 mg (392 μmol) of the compound that ispresented according to Example 12i is reacted, and after working-up andpurification, 323 mg (314 μmol, 80%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=−0.03-0.12 (24H), 0.79-1.73 (53H), 1.61+1.69 (3H),1.91-2.07 (2H), 2.00 (3H), 2.26 (2H), 2.71 (3H), 2.86 (1H), 2.98 (1H),3.33-3.55 (2H), 3.66 (1H), 3.80 (1H), 4.10 (1H), 5.17 (1H), 6.47 (1H),6.91 (1H), 7.06-7.29 (H) ppm.

EXAMPLE 12l(3S,6R,7S,8S,12E/Z,15S,16E)-6-Benzyl-1-hydroxy-17-(2-methyl-4-thiazolyl)-4,4,8,12,16-pentamethyl-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-heptadeca-12,16-dien-5-one

Analogously to Example 1ar, 432 mg (420 μmol) of the compound that ispresented according to Example 12 is reacted, and after working-up andpurification, 264 mg (289 μmol, 69%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=−0.03-0.12 (18H), 0.53 (1H), 0.78-1.40 (41H),1.62+1.71 (3H), 1.42-1.81 (2H), 2.00 (3H), 1.92-2.10 (2H), 2.27 (2H),2.70 (3H), 2.852 (1H), 3.09 (1H), 3.30 (2H), 3.40 (1H), 3.70 (1H), 3.81(1H), 4.11 (1H), 5.17 (1H), 6.46 (1H), 6.91 (1H), 7.11-7.30 (5H) ppm.

EXAMPLE 12m(3S,6R,7S,8S,12E/Z,15S,16E)-6-Benzyl-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-methyl-4-thiazolyl)-5-oxo-heptadeca-12,16-dienoicAcid

Analogously to Example 1k, 264 mg (289 μmol) of the compound that ispresented according to Example 12l is reacted, and after working-up, 255mg (279 μmol, 97%) of the title compound is isolated as a colorless oil,which is further reacted without purification.

EXAMPLE 12n(3S,6R,7S,8S,12Z,15S,16E)-6-Benzyl-17-(2-methyl-4-thiazolyl)-5-oxo-4,4,8,12,16-pentamethyl-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-heptadeca-12,16-dienoicacid (A) and(3S,6R,7S,8S,12E,15S,16E)-6-benzyl-17-(2-methyl-4-thiazolyl)-5-oxo-4,4,8,12,16-pentamethyl-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-heptadeca-12,16-dienoicacid (B)

Analogously to Example 1at, 255 mg (279 μmol) of the compound that ispresented according to Example 12m is reacted, and after working-up andpurification, 61 mg (66 μmol, 24%) of title compound A is isolated as acolorless solid, and 54 mg (58 μmol, 21%) of title compound B isisolated as a colorless oil.

¹H-NMR (CDCl₃) of A: δ=−0.07-0.18 (18H), 0.60 (3H), 0.78 (3H), 0.82(9H), 0.89 (9H), 0.92 (9H), 1.07 (3H), 1.72 (3H), 1.95 (3H), 0.74-2.33(12H), 2.69 (3H), 2.91 (1H), 3.03 (1H), 3.41 (1H), 3.62 (1H), 4.20 (1H),4.30 (1H), 5.23 (1H), 6.72 (1H), 6.96 (11H), 7.05-7.29 (5H) ppm.

¹H-NMR (CDCl₃) of B: δ=−0.08-0.14 (18H), 0.72 (3H), 0.82 (3H), 0.85(9H), 0.90 (9H), 0.93 (9H), 0.98 (3H), 1.60 (3H), 0.65-2.08 (9H), 1.96(3H), 2.12 (1H), 2.29 (2H), 2.71 (3H), 2.92 (2H), 3.47 (1H), 3.69 (1H),4.09 (1H), 4.21 (1H), 5.12 (1H), 6.49 (1H), 6.95 (1H), 7.06-7.30 (5H)ppm.

EXAMPLE 12o(3S,6R,7S,8S,12Z,15S,16E)-6-Benzyl-15-hydroxy-17-(2-methyl-4-thiazolyl)-5-oxo-4,4,8,12,16-pentamethyl-3,7-bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-heptadeca-12,16-dienoicacid

Analogously to Example 1i, 61 mg (66 μmol) of compound A that ispresented according to Example 12n is reacted at 23° C., and afterworking-up and purification, 33 mg (41 μmol, 61%) of the title compoundis isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=−0.11 (3H), −0.08-0.05 (9H), 0.80 (9H), 0.88 (9H),0.91 (3H), 0.94 (3H), 0.99 (3H), 1.72 (3H), 1.98 (3H), 0.77-2.22 (12H),2.69 (3H), 2.70-2.91 (2H), 3.39 (1H), 3.62 (1H), 4.18 (1H), 4.33 (1H),4.43-5.73 (1H), 5.13 (1H), 6.68 (1H), 6.91 (1H), 7.05-7.26 (5H) ppm.

EXAMPLE 12p(4S,7R,8S,9S,13Z,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-7-benzyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1aw, 33 mg (40 μmol) of the compound that ispresented according to Example 12o is reacted, and after working-up andpurification, 17 mg (21 μmol, 53%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=−0.06 (3H), 0.00 (3H), 0.07 (3H), 0.09 (3H), 0.98(3H), 1.71 (3H), 2.10 (3H), 0.70-2.48 (34H), 2.63 (1H), 2.71 (3H), 2.81(2H), 3.23 (1H), 3.76 (1H), 4.17 (1H), 5.13 (2H), 6.56 (1H), 6.95 (1H),7.06-7.32 (5H) ppm.

EXAMPLE 12(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-benzyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 12.2 mg (9.7 μmol) of the compound that ispresented according to Example 12p is reacted, and after working-up andpurification, 5.0 mg (8.8 μmol, 91%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.61 (3H), 0.83 (3H), 1.11 (3H), 1.22-2.00 (5H), 1.71(3H), 2.05 (3H), 2.19-2.49 (5H), 2.61 (1H), 2.66 (3H), 2.89 (1H), 3.03(1H), 3.59 (1H), 3.67 (1H), 4.21 (1H), 5.10 (1H), 5.24 (1H), 6.53 (1H),6.92 (1H), 7.07-7.31 (5H) ppm.

EXAMPLE 13(4S,7R,8S,9S,13E,16S(E))-4,8-Dihydroxy-7-benzyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dioneEXAMPLE 13a(3S,6R,7S,8S,12E,15S,16E)-6-Benzyl-15-hydroxy-17-(2-methyl-4-thiazolyl)-5-oxo-4,4,8,12,16-pentamethyl-3,7-bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-heptadeca-12,16-dienoicacid

Analogously to Example 1i, 47 mg (51 μmol) of compound B that ispresented according to Example 12n is reacted at 23° C., and afterworking-up and purification, 22 mg (27 μmol, 53%) of the title compoundis isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=−0.08 (3H), −0.03-0.09 (9H), 0.82 (9H), 0.89 (12H),0.97 (6H), 1.64 (3H), 2.02 (3H), 0.78-2.10 (9H), 2.27-2.46 (2H), 2.70(3H), 2.82 (2H), 2.92-3.34 (2H), 3.42 (1H), 3.67 (1H), 4.19 (1H), 4.32(1H), 5.28 (1H), 6.63 (1H), 6.92 (1H), 7.02-7.27 (5H) ppm.

EXAMPLE 13b(4S,7R,8S,9S,13E,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-7-benzyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1aw, 22 mg (27 μmol) of the compound that ispresented according to Example 13a is reacted, and after working-up andpurification, 12 mg (15 μmol, 56%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=−0.04 (3H), 0.06 (6H), 0.12 (3H), 0.80 (3H), 0.88(9H), 0.90 (9H), 0.96 (3H), 1.08 (3H), 1.64 (3H), 0.74-1.72 (4H),1.80-2.27 (5H), 2.09 (3H), 2.33 (1H), 2.53-2.82 (2H), 2.70 (3H), 2.96(1H), 3.20 (1H), 3.74 (1H), 4.15 (1H), 5.19-5.32 (2H), 6.47 (1H), 6.90(1H), 7.07-7.31 (5H) ppm.

EXAMPLE 13(4S,7R,8S,9S,13E,16S(E))-4,8-Dihydroxy-7-benzyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 12 mg (15 μmol) of the compound that ispresented according to Example 13b is reacted, and after working-up andpurification, 6.0 mg (11 μmol, 69%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=0.69 (3H), 0.72 (3H), 0.89 (1H), 1.08 (3H), 1.38-1.69(3H), 1.61 (3H), 1.90-2.12 (2H), 2.02 (3H), 2.19 (1H), 2.25-2.44 (3H),2.54 (1H), 2.69 (3H), 2.79 (1H), 2.99 (1H), 3.73 (2H), 4.25-4.39 (2H),4.66 (1H), 5.03 (1H), 5.34 (1H), 6.52 (1H), 6.97 (1H), 7.04-7.29 (5H)ppm.

EXAMPLE 14(1S,3S(E),7S,10R,11S,12S,16R)-10-Benzyl-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(E),7S,10R,11S,12S,16S)-10-benzyl-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(B)

The solution of 4.0 mg (7.0 μmol) of the compound, presented accordingto Example 12, in 0.1 ml of acetonitrile is mixed with 38 μl of a 1 Msolution of sodium ethylenediamine tetraacetate, cooled to 0° C., andmixed with 67 μl of 1,1,1-trifluoroacetone as well as a mixture of 21 mgof oxone and 4.5 mg of sodium bicarbonate. It is allowed to react for 5hours, poured onto sodium thiosulfate solution and extracted severaltimes with ethyl acetate. The combined organic extracts are washed withsaturated sodium chloride solution, and the residue that is obtainedafter filtration and removal of the solvent is purified bychromatography on an analytic thin-layer plate. As a mobile solvent, amixture of n-hexane and ethyl acetate is used. 2.2 mg (3.8 μmol, 54%) oftitle compound A and 0.3 mg (0.5 μmol, 7%) of title compound B areisolated in each case as a colorless oil.

¹H-NMR (CDCl₃) of A: δ=0.67 (3H), 0.80 (3H), 1.07 (3H), 1.29 (3H),1.35-2.06 (9H), 2.09 (3H), 2.33 (1H), 2.49 (1H), 2.68 (3H), 2.72-2.85(2H), 3.04 (1H), 3.40 (1H), 3.62 (1H), 3.77 (1H), 4.22 (1H), 4.51 (1H),5.47 (1H), 6.51 (1H), 6.95 (1H), 7.06-7.30 (5H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.68 (3H), 0.76 (3H), 0.86 (1H), 1.07 (3H),1.23-2.13 (7H), 1.30 (3H), 2.08 (3H), 2.30-2.49 (2H), 2.70 (3H),2.87-3.11 (3H), 3.28 (2H), 3.57 (1H), 3.93 (1H), 4.21 (1H), 4.54-5.73(1H), 5.58 (1H), 6.58 (1H), 6.97 (1H), 7.07-7.31 (5H) ppm.

EXAMPLE 15(1S,3S(E),7S,10R,11S,12S,16S)-10-Benzyl-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(E),7S,10R,11S,12S,16R)-10-benzyl-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 14, 3.1 mg (5.4 μmol) of the compound that ispresented according to Example 13 is reacted, and after working-up andpurification, 0.7 mg (1.2 μmol, 22%) of title compound A or B and 0.6 mg(1.0 μmol, 19%) of title compound B or A are isolated as colorless oils.

¹H-NMR (CDCl₃) of A or B: δ=0.76 (3H), 0.88 (3H), 1.02 (3H), 1.24 (1H),1.30 (3H), 1.38-1.78 (5H), 1.92-2.13 (3H), 2.07 (3H), 2.44 (2H), 2.70(3H), 2.78-2.87 (2H), 3.04 (1H), 3.60 (1H), 3.71-3.80 (2H), 4.01 (1H),4.28 (1H), 5.45 (1H), 6.62 (1H), 6.99 (1H), 7.11-7.31 (5H) ppm.

¹H-NMR (CDCl₃) of B or A: δ=0.70 (3H), 0.76 (3H), 1.06 (3H), 1.19-1.64(5H), 1.22 (3H), 1.80 (1H), 1.90-2.12 (3H), 2.07 (3H), 2.46 (2H), 2.69(3H), 2.79 (1H), 2.92 (1H), 3.08 (1H), 3.32 (1H), 3.57 (1H), 3.62 (1H),3.71 (1H), 4.12 (1H), 5.42 (1H), 6.54 (1H), 6.96 (1H), 7.06-7.31 (5H)ppm.

EXAMPLE 16(4S,7S,8R,9S,13Z,16S(E))-4,8-Dihydroxy-7-benzyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dioneEXAMPLE 16a(4S(4S,5R,6S,10RS))-4-(2,6-Dimethyl-10-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4-benzyl-3-oxo-5-(tetrahydropyran-2-yloxy)-undec-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1a, 1.71 g (2.59 mmol) of compound B that ispresented according to Example 12c is reacted, and after working-up andpurification, 1.51 g (1.99 mmol, 77%) of the title compound is isolatedas a colorless oil.

EXAMPLE 16b(4S(4S,5R,6S,10RS))-4-(2,6-Dimethyl-4-benzyl-10-hydroxy-3-oxo-5-(tetrahydropyran-2-yloxy)-undec-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1i, 1.51 g (1.99 mmol) of the compound that ispresented according to Example 16a is reacted, and after working-up andpurification, 855 mg (1.65 mmol, 83%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.88+0.92 (3H), 0.92-1.95 (32H), 2.82-3.10 (2H),3.32-3.59 (2H), 3.71-3.98 (5H), 4.43-4.59 (1H), 7.11-7.31 (5H) ppm.

EXAMPLE 16c(4S(4S,5R,6S))-4-(2,6-Dimethyl-4-benzyl-3,10-dioxo-5-(tetrahydropyran-2-yloxy)-undec-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1m, 850 mg (1.64 mmol) of the compound that ispresented according to Example 16b is reacted, and after working-up andpurification, 741 mg (1.43 mmol, 88%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.84+0.90 (3H), 0.95+1.05 (3H), 0.97 (3H), 1.8-1.88(19H), 2.15 (3H), 2.42 (2H), 2.79-3.08 (2H), 3.31-3.57 (2H), 3.69-3.96(5H), 4.43+4.52 (1H), 7.10-7.29 (5H) ppm.

EXAMPLE 16d(4S(4S,5R,6S,10E/Z,13S,14E))-4-(13-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-benzyl-15-(2-methyl-4-thiazolyl)-3-oxo-5-(tetrahydropyran-2-yloxy)-2,6,10,14-tetramethyl-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1ao, 737 mg (1.43 mmol) of the compound that ispresented according to Example 16c is reacted with use of n-butyllithiumas a base, and after working-up and purification, 491 mg (525 μmol, 37%)of the title compound is isolated as a colorless oil.

EXAMPLE 16e(4S(4S,5R,6S,10E/Z,13S,14E))-4-(4-Benzyl-13-hydroxy-15-(2-methyl-4-thiazolyl)-3-oxo-5-(tetrahydropyran-2-yloxy)-2,6,10,14-tetramethyl-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1i, 1.09 g (1.17 mmol) of the compound that ispresented according to Example 16d is reacted, and after working-up andpurification, 677 mg (973 μmol, 83%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.78-2.12 (31H), 1.67+1.73 (3H), 2.06 (3H), 2.36 (2H),2.71 (3H), 2.81-3.08 (2H), 3.30-3.52 (2H), 3.69-3.96 (5H), 4.14 (1H),4.43+4.51 (1H), 5.20 (1H), 6.57 (1H), 6.95 (1H), 7.08-7.30 (5H) ppm.

EXAMPLE 16f(3S,6S,7R,8S,12E/Z,15S,16E)-6-Benzyl-17-(2-methyl-4-thiazolyl)-5-oxo-4,4,8,12,16-pentamethyl-heptadeca-12,16-diene-1,3,7,15-tetraol

Analogously to Example 1f, 675 mg (970 μmol) of the compound that ispresented according to Example 16e is reacted, and after working-up andpurification, 495 mg (866 μmol, 89%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.73-0.86 (6H), 0.96-1.10 (3H), 1.21-1.79 (7H),1.67+1.76 (3H), 1.98-2.17 (5H), 2.28-2.50 (3H), 2.70 (3H), 2.85 (1H),2.97 (1H), 3.09 (1H), 3.40-3.87 (7H), 4.16 (1H), 5.27 (1H), 6.51+6.57(1H), 6.94 (1H), 7.07-7.30 (5H) ppm.

EXAMPLE 16g(3S,6S,7R,8S,12E/Z,15S,16E)-6-Benzyl-17-(2-methyl-4-thiazolyl)-4,4,8,12,16-pentamethyl-1,3,7,15-tetrakis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-heptadeca-12,16-dien-5-one

Analogously to Example 1aq, 337 mg (589 μmol) of the compound that ispresented according to Example 16f is reacted, and after working-up andpurification, 444 mg (432 μmol, 73%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=−0.08-0.13 (24H), 0.42 (3H), 0.79-1.03 (42H),1.11-1.73 (8H), 1.60+1.67 (3H), 1.90-2.08 (4H), 2.26 (2H), 2.71 (3H),2.91 (2H), 3.22 (1H), 3.50-3.72 (3H), 3.85 (1H), 4.09 (1H), 5.16 (1H),6.46 (1H), 6.91 (1H), 7.07-7.27 (5H) ppm.

EXAMPLE 16h(3S,6S,7R,8S,12E/Z,15S,16E)-6-Benzyl-1-hydroxy-17-(2-methyl-4-thiazolyl)-4,4,8,12,16-pentamethyl-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-heptadeca-12,16-dien-5-one

Analogously to Example 1ar, 444 mg (432 μmol) of the compound that ispresented according to Example 16g is reacted, and after working-up andpurification, 272 mg (297 μmol, 69%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=−0.07-0.18 (18H), 0.48 (3H), 0.79-1.72 (40H),1.61+1.68 (3H), 1.81 (1H), 1.90-2.09 (5H), 2.26 (2H), 2.70 (3H),2.86-3.04 (2H), 3.23 (1H), 3.59 (2H), 3.70 (1H), 3.91 (1H), 4.10 (1H),5.16 (1H), 6.44 (1H), 6.91 (1H), 7.08-7.29 (5H) ppm.

EXAMPLE 16i(3S,6S,7R,8S,12E/Z,15S,16E)-6-Benzyl-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-methyl-4-thiazolyl)-5-oxo-heptadeca-12,16-dienoicacid

Analogously to Example 1k, 272 mg (297 μmol) of the compound that ispresented according to Example 16h is reacted, and after working-up, 264mg (289 μmol, 97%) of the title compound is isolated as a colorless oil,which is further reacted without purification.

EXAMPLE 16k(3S,6S,7R,8S,12Z,15S,16E)-6-Benzyl-17-(2-methyl-4-thiazolyl)-5-oxo-4,4,8,12,16-pentamethyl-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-heptadeca-12,16-dienoicacid (A) and(3S,6S,7R,8S,12E,15S,16E)-6-benzyl-17-(2-methyl-4-thiazolyl)-5-oxo-4,4,8,12,16-pentamethyl-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-heptadeca-12,16-dienoicacid (B)

Analogously to Example 1at, 264 mg (289 μmol) of the compound that ispresented according to Example 16i is reacted, and after working-up andpurification, 87 mg (94 μmol, 32%) of title compound A and 67 mg (73μmol, 25%) of title compound B are isolated in each case as a colorlessoil.

¹H-NMR (CDCl₃) of A: δ=−0.09 (3H), −0.02-0.13 (15H), 0.69 (3H),0.80-1.48 (32H), 1.03 (3H), 1.63-1.79 (1H), 1.68 (3H), 2.00 (3H),1.91-2.09 (2H), 2.12-2.33 (3H), 2.72 (3H), 2.77-3.20 (6H), 3.31 (1H),3.70 (1H), 4.10 (1H), 4.43 (1H), 5.16 (1H), 6.47 (1H), 6.91 (1H),7.08-7.29 (5H) ppm.

¹H-NMR (CDCl₃) of B: δ=−0.10 (3H), −0.03-0.17 (15H), 0.68 (3H),0.80-1.50 (33H), 1.02 (3H), 1.61 (3H), 1.71 (2H), 1.88-2.07 (2H), 2.00(3H), 2.11-2.68 (4H), 2.71 (3H), 2.86 (2H), 3.30 (1H), 3.69 (1H),3.75-4.08 (1H), 4.11 (1H), 4.43 (1H), 5.16 (1H), 6.47 (1H), 6.91 (1H),7.08-7.30 (5H) ppm.

EXAMPLE 16l(3S,6S,7R,8S,12Z,15S,16E)-6-Benzyl-15-hydroxy-17-(2-methyl-4-thiazolyl)-5-oxo-4,4,8,12,16-pentamethyl-3,7-bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-heptadeca-12,16-dienoicacid

Analogously to Example 1i, 87 mg (94 μmol) of compound A that ispresented according to Example 16k is reacted at 23° C., and afterworking-up and purification, 76 mg (93 μmol, 99%) of the title compoundis isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=−0.03-0.13 (12H), 0.52 (3H), 0.78-1.80 (28H), 1.73(3H), 1.91-2.17 (2H), 2.00 (3H), 2.21 (2H), 2.34 (2H), 2.69-3.01 (3H),2.73 (3H), 3.19 (1H), 3.31 (1H), 3.74 (1H), 4.13 (1H), 4.28-5.68 (1H),4.36 (1H), 5.18 (1H), 6.62 (1H), 6.97 (1H), 7.08-7.31 (5H) ppm.

EXAMPLE 16m(4S,7S,8R,9S,13Z,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-7-benzyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1aw, 76 mg (93 μmol) of the compound that ispresented according to Example 16l is reacted, and after working-up andpurification, 68 mg (85 μmol, 92%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=−0.02 (3H), 0.01 (3H), 0.16 (3H), 0.30 (3H), 0.54(3H), 0.64 (3H), 0.85 (9H), 0.97 (9H), 0.99 (3H), 0.80-1.75 (5H), 1.69(3H), 1.89 (1H), 1.98-2.31 (3H), 2.13 (3H), 2.37 (1H), 2.52 (1H), 2.70(1H), 2.72 (3H), 3.10 (1H), 3.46 (1H), 3.96 (1H), 4.05 (1H), 5.10 (1H),5.15 (1H), 6.48 (1H), 7.02 (1H), 7.09-7.31 (5H) ppm.

EXAMPLE 16(4S,7S,8R,9S,13Z,16S(E))-4,8-Dihydroxy-7-benzyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 10 mg (13 μmol) of the compound that ispresented according to Example 12p is reacted, and after working-up andpurification, 6.3 mg (11 μmol, 89%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=0.47 (3H), 0.84 (1H), 0.97 (3H), 1.04 (3H), 1.22-1.70(4H), 1.76 (3H), 1.94 (1H), 1.93 (3H), 2.22-2.49 (4H), 2.61-2.77 (1H),2.71 (3H), 2.83 (1H), 2.90 (1H), 3.02 (1H), 3.08 (1H), 3.59 (1H), 3.62(1H), 4.18 (1H), 5.19 (1H), 5.53 (1H), 6.50 (1H), 6.96 (1H), 7.08-7.31(5H) ppm.

EXAMPLE 17(4S,7S,8R,9S,13E,16S(E))-4,8-Dihydroxy-7-benzyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dioneEXAMPLE 17a(3S,6S,7R,8S,12E,15S,16E)-6-Benzyl-15-hydroxy-17-(2-methyl-4-thiazolyl)-5-oxo-4,4,8,12,16-pentamethyl-3,7-bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-heptadeca-12,16-dienoicAcid

Analogously to Example 1i, 67 mg (72 μmol) of compound B that ispresented according to Example 16k is reacted at 23° C., and afterworking-up and purification, 57 mg (70 μmol, 97%) of the title compoundis isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=−0.06-0.13 (12H), 0.47 (3H), 0.77-1.76 (28H), 1.64(3H), 1.90-2.07 (2H), 2.00 (3H), 2.28 (2H), 2.39 (2H), 2.66-2.89 (2H),2.73 (2H), 2.91-3.05 (3H), 3.19 (1H), 3.29 (1H), 3.76 (1H), 4.20 (1H),4.36 (1H), 5.16 (1H), 6.58 (1H), 6.94 (1H), 7.07-7.31 (5H) ppm.

EXAMPLE 17b(4S,7S,8R,9S,13E,16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-7-benzyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1aw, 57 mg (70 μmol) of the compound that ispresented according to Example 17a is reacted, and after working-up andpurification, 32 mg (40 μmol, 57%) of the title compound is isolated asa colorless solid.

¹H-NMR (CDCl₃): δ=0.07 (9H), 0.23 (3H), 0.53 (3H), 0.72 (3H), 0.88 (9H),0.93 (9H), 0.98 (3H), 1.08-1.30 (2H), 1.39 (1H), 1.48-1.86 (3H), 1.61(3H), 2.10 (3H), 2.07-2.27 (2H), 2.31-2.58 (3H), 2.63-2.78 (1H), 2.71(3H), 3.08 (1H), 3.41 (1H), 3.82 (1H), 4.19 (1H), 5.08 (1H), 5.15 (1H),6.51 (1H), 7.02 (1H), 7.08-7.30 (5H) ppm.

EXAMPLE 17(4S,7S,8R,9S,13E,16S(E))-4,8-Dihydroxy-7-benzyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 32 mg (40 μmol) of the compound that ispresented according to Example 17b is reacted, and after working-up andpurification, 16.6 mg (29 μmol, 73%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.35 (3H), 0.91 (3H), 0.93 (3H), 1.61 (3H), 0.83-1.72(5H), 1.94-2.20 (2H), 2.09 (3H), 2.32 (1H), 2.46 (1H), 2.51 (2H), 2.69(3H), 2.90-3.02 (3H), 3.13 (1H), 3.55-3.68 (2H), 4.23 (1H), 5.11 (1H),5.43 (1H), 6.47 (1H), 6.92 (1H), 7.07-7.31 (5H) ppm.

EXAMPLE 18(1S,3S(E),7S,10S,11R,12S,16R)-10-Benzyl-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(E),7S,10S,11R,12S,16S)-10-benzyl-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 14, 1.4 mg (2.5 μmol) of the compound that ispresented according to Example 16 is reacted, and after working-up andpurification, 0.3 mg (0.5 μmol, 21%) of title compounds A and B isisolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.27 (3H), 0.98 (3H), 1.08 (3H), 1.23 (3H), 1.15-2.46(10H), 2.19 (3H), 2.71 (3H), 2.82 (1H), 2.91 (1H), 2.95 (1H), 3.10 (1H),3.47 (1H), 3.95 (1H), 4.12 (1H), 4.42 (1H), 4.70-5.30 (1H), 5.60 (1H),6.65 (1H), 7.00 (1H), 7.12-7.32 (5H) ppm.

EXAMPLE 19(1S,3S(E),7S,10S,11R,12S,16S)-10-Benzyl-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(E),7S,10S,11R,12S,16R)-10-benzyl-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 14, 7.4 mg (13 μmol) of the compound that ispresented according to Example 17 is reacted, and after working-up andpurification, 1.9 mg (3.3 μmol, 25%) of title compound A and 1.7 mg (2.9μmol, 22%) of title compound B are isolated in each case as a colorlessoil.

¹H-NMR (CDCl₃) of A: δ=0.40 (3H), 0.89 (3H), 0.97 (3H), 1.08-1.77 (6H),1.22 (3H), 1.90-2.07 (3H), 2.08 (3H), 2.38 (1H), 2.57 (1H), 2.70 (3H),2.83 (1H), 2.92-3.06 (3H), 3.19 (1H), 3.54 (1H), 3.77 (1H), 4.19 (1H),5.53 (1H), 6.52 (1H), 6.97 (1H), 7.08-7.31 (5H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.17 (3H), 0.89 (3H), 1.00 (3H), 1.21-1.97 (8H),1.28 (3H), 2.06 (1H), 2.10 (3H), 2.27-2.44 (3H), 2.71 (3H), 2.90 (1H),2.99-3.11 (2H), 3.36 (1H), 3.96 (1H), 4.20 (1H), 4.29 (1H), 5.77 (1H),6.57 (1H), 6.98 (1H), 7.08-7.31 (5H) ppm.

EXAMPLE 20(4S,7R,8S,9S,13(Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dioneEXAMPLE 20a(5E,3S)-[3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-methyl-5-(2-pyridyl)-pent-4-en-1-yl]-triphenylphosphoniumiodide

Analogously to Examples 7a to 7d, the title compound is obtained as acrystalline solid with use of diethyl(2-pyridyl)methanephosphonate.

¹H-NMR (CDCl₃): δ=1.08 (9H), 1.70-1.95 (2H), 1.99 (1H), 3.00 (1H), 3.31(1H), 4.59 (1H), 6.68 (1H), 7.10 (1H), 7.18-7.46 (8H), 7.50-7.74 (18H),7.74-7.87 (3H), 8.57 (1H) ppm.

EXAMPLE 20b(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-15-(2-pyridyl)-3-oxo-5-(tetrahydropyran-2-yloxy)-2,4,6,10,14-pentamethyl-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1ao, 2.9 g (6.58 mmol) of the compound(4S(4R,5S,6S))-4-(3,10-dioxo-2,4,6-trimethyl-5-(tetrahydropyran-2-yloxy)-undec-2-yl)-2,2-dimethyl-[1,3]dioxanethat is produced analogously to Examples 1l (reaction withethylmagnesium bromide) to 1an is reacted with 8.0 g (9.95 mmol) of thecompound that is described under Example 20a and 7.54 ml of a 1.6 Msolution of n-butyllithium in n-hexane. In addition to startingmaterial, 1.71 g (2.0 mmol, 31%) of the title compound is obtained.

¹H-NMR (CDCl₃): δ=0.84-0.98 (3H), 0.99-1.97 (42H), 2.01 (3H), 2.29 (2H),3.22 (1H), 3.41 (1H), 3.58-4.01 (4H), 4.07-4.22 (2H), 4.47+4.51 (1H),5.01 (1H), 6.24 (1H), 7.07 (1H), 7.22-7.46 (7H), 7.52-7.75 (5H), 8.57(1H) ppm.

EXAMPLE 20c(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-Hydroxy-15-(2-pyridyl)-3-oxo-5-(tetrahydropyran-2-yloxy)-2,4,6,10,14-pentamethyl-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1i, 1.76 g (2.11 mmol) of the compound that ispresented according to Example 20b is reacted, and after working-up andpurification, 1.17 g (1.95 mmol, 93%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.88-2.13 (37H), 2.09 (3H), 2.39 (2H), 3.26 (1H), 3.44(1H), 3.75-4.02 (3H), 4.08-4.22 (2H), 4.48+4.55 (1H), 5.21 (1H), 6.60(1H), 7.10 (1H), 7.25 (1H), 7.64 (1H), 8.60 (1H) ppm.

EXAMPLE 20d(3S,6R,7S,8S,12E/Z,15S,16E)-1,3,7,15-Tetrahydroxy-4,4,6,8,12,16-hexamethyl-17-(2-pyridyl)-heptadeca-12,16-dien-5-one

Analogously to Example 1f, 1.17 g (1.95 mmol) of the compound that ispresented according to Example 20c is reacted with use ofp-toluenesulfonic acid-monohydrate, and after working-up andpurification, 852 mg (1.79 mmol, 92%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.83+0.88 (3H), 1.06 (3H), 1.12 (3H), 1.22 (3H),1.63+1.72 (3H), 0.98-1.82 (7H), 1.96-2.21 (3H), 2.07 (3H), 2.39 (2H),2.90-3.80 (2H), 3.28 (1H), 3.32-3.48 (2H), 3.89 (2H), 4.06 (1H), 4.18(1H), 5.20 (1H), 6.59 (1H), 7.11 (1H), 7.28 (1H), 7.64 (1H), 8.59 (1H)ppm.

EXAMPLE 20e(3S,6R,7S,8S,12E/Z,15S,16E)-1,3,7,15-Tetrakis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-pyridyl)-heptadeca-12,16-dien-5-one

Analogously to Example 1aq, 847 mg (1.78 mmol) of the compound that ispresented according to Example 20d is reacted, and after working-up andpurification, 1.32 g (1.42 mmol, 80%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=−0.02-0.13 (24H), 0.80-0.97 (39H), 1.02 (3H), 1.04(3H), 1.21 (3H), 1.59+1.68 (3H), 1.08-1.70 (7H), 1.89-2.08 (2H), 2.06(3H), 2.28 (2H), 3.13 (1H), 3.52-3.74 (2H), 3.77 (1H), 3.89 (1H), 4.11(1H), 5.18 (1H), 6.48 (1H), 7.08 (1H), 7.21 (1H), 7.62 (1H), 8.60 (1H)ppm.

EXAMPLE 20f(3S,6R,7S,8S,12E/Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-1-hydroxy-17-(2-pyridyl)-heptadeca-12,16-dien-5-one

Analogously to Example 1ar, 1.32 g (1.42 mmol) of the compound that ispresented according to Example 20e is reacted, and after working-up andpurification, 1.06 g (1.29 mmol, 91%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.00-0.13 (18H), 0.80-0.97 (30H), 1.06 (6H), 1.00-1.63(7H), 1.21 (3H), 1.58+1.68 (3H), 1.89-2.08 (3H), 2.04 (3H), 2.28 (2H),3.12 (1H), 3.63 (2H), 3.79 (1H), 4.02-4.16 (2H), 5.18 (1H), 6.48 (1H),7.08 (1H), 7.21 (1H), 7.61 (1H), 8.60 (1H) ppm.

EXAMPLE 20g(3S,6R,7S,8S,12E/Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-pyridyl)-5-oxo-heptadeca-12,16-dienal

Analogously to Example 1k, 1.14 g (1.39 mmol) of the compound that ispresented according to Example 20f is reacted, and after working-up,1.10 q (1.35 mmol, 97%) of the title compound is isolated as a colorlessoil, which is further reacted without purification.

EXAMPLE 20h(3S,6R,7S,8S,12E,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-pyridyl)-5-oxo-heptadeca-12,16-dienoicacid (A) and(3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-pyridyl)-5-oxo-heptadeca-12,16-dienoicacid (B)

Analogously to Example 1at, 1.10 g (1.35 mmol) of the compound that ispresented according to Example 20g is reacted, and after working-up andpurification, 467 mg (0.56 mmol, 42%) of title compound B and 374 mg(0.45 mmol, 33%) of title compound A are isolated in each case as acolorless oil.

¹H-NMR (CDCl₃) of A: δ=0.00-0.19 (18H), 0.85 (3H), 0.90 (27H), 1.01-1.50(6H), 1.07 (3H), 1.15 (3H), 1.21 (3H), 1.57 (3H), 1.81-2.08 (1H), 1.96(3H), 2.24-2.41 (4H), 2.60 (1H), 3.18 (1H), 3.83 (1H), 4.13 (1H), 4.38(1H), 5.13 (1H), 6.50 (1H), 7.16 (1H), 7.36 (1H), 7.71 (1H), 8.61 (1H)ppm.

¹H-NMR (CDCl₃) of B: δ=−0.02-0.17 (18H), 0.80-0.98 (30H), 1.00-1.59(6H), 1.05 (3H), 1.13 (3H), 1.18 (3H), 1.69 (3H), 1.81-1.98 (1H), 1.91(3H), 2.10-2.40 (4H), 2.49 (1H), 3.10 (1H), 3.79 (1H), 4.15 (1H), 4.42(1H), 5.21 (1H), 6.63 (1H), 7.17 (1H), 7.31 (1H), 7.70 (1H), 8.58 (1H)ppm.

EXAMPLE 20i(3S,6R,7S,8S,12Z,15S,16E)-3,7-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-15-hydroxy-17-(2-pyridyl)-5-oxo-heptadeca-12,16-dienoicacid

Analogously to Example 1i, 405 mg (0.49 mmol) of compound B that ispresented according to Example 20h is reacted, and after working-up andpurification, 338 mg (0.47 mmol, 96%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.00-0.15 (12H), 0.80-0.99 (21H), 1.02-1.60 (6H), 1.07(3H), 1.14 (3H), 1.19 (3H), 1.72 (3H), 1.90-2.08 (1H), 1.99 (3H), 2.17(1H), 2.31 (1H), 2.38 (2H), 2.49 (1H), 3.00-4.00 (1H), 3.12 (1H), 3.81(1H), 4.19 (1H), 4.43 (1H), 5.24 (1H), 6.73 (1H), 7.18 (1H), 7.32 (1H),7.71 (1H), 8.60 (1H) ppm.

EXAMPLE 20j(4S,7R,8S,9S,13(Z),16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1aw, 287 mg (0.40 mmol) of the compound that ispresented according to Example 20i is reacted, and after working-up andpurification, 144 mg (0.21 mmol, 51%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=−0.09 (3H), 0.01-0.18 (9H), 0.79-1.32 (4H), 0.85 (9H),0.94 (9H), 0.98 (3H), 1.10 (3H), 1.14 (3H), 1.20 (3H), 1.46-1.82 (3H),1.69 (3H), 2.03-2.21 (1H), 2.15 (3H), 2.49 (1H), 2.62-2.88 (2H), 3.03(1H), 3.90 (1H), 4.05 (1H), 5.02 (1H), 5.19 (1H), 6.58 (1H), 7.11 (1H),7.27 (1H), 7.65 (1H), 8.61 (1H) ppm.

EXAMPLE 20(4S,7R,8S,9S,13(Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 144 mg (206 μmol) of the compound that ispresented according to Example 20j is reacted, and after working-up andpurification, 90 mg (191 μmol, 93%) of the title compound is isolated asa colorless oil.

¹H-NMR (CDCl₃): δ=1.02 (3H), 1.08 (3H), 1.20 (3H), 1.24-1.43 (4H), 1.38(3H), 1.67 (3H), 1.60-1.98 (2H), 2.06 (3H), 2.23 (1H), 2.31 (2H), 2.45(1H), 2.64 (1H), 3.11-3.27 (2H), 3.73 (1H), 4.41 (1H), 4.50-4.77 (1H),5.09-5.23 (2H), 6.62 (1H), 7.14 (1H), 7.31 (1H), 7.69 (1H), 8.52 (1H)ppm.

EXAMPLE 21(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(B) and(4S,7R,8S,9S,13(Z),16S(E))-4,8-dihydroxy-16-(1-methyl-2-(2-N-oxypyridyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione(C) and(1S,3S(E),7S,10R,11S,12S,16R)-7,11-dihydroxy-3-(1-methyl-2-(2-N-oxypyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(D) and(1R,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-N-oxypyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(E)

Analogously to Example 14, 40 mg (84 μmol) of the compound that ispresented according to Example 20 is reacted, and after working-up andpurification, 8.5 mg (17 μmol, 21%) of title compound A, 2.0 mg (4 μmol,5%) of title compound B, 2.9 mg (6 μmol, 7%) of title compound C, 12.6mg (25 μmol, 30%) of title compound D, and 2.5 mg (5 μmol, 6%) of titlecompound E are isolated.

¹H-NMR (CDCl₃) of A: δ=1.00 (3H), 1.08 (3H), 1.16 (3H), 1.21-1.98 (9H),1.29 (3H), 1.38 (3H), 2.07 (3H), 2.19 (1H), 2.30 (1H), 2.53 (1H), 2.81(1H), 2.89 (1H), 3.29 (1H), 3.76 (1H), 4.37 (1H), 5.40 (1H), 6.53 (1H),7.16 (1H), 7.29 (1H), 7.70 (1H), 8.53 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.94 (3H), 1.03 (3H), 1.11 (3H), 1.28 (3H), 1.38(3H), 1.00-1.95 (8H), 2.14 (3H), 2.08-2.20 (1H), 2.41 (1H), 2.49 (1H),2.83 (1H), 3.09 (1H), 3.33 (1H), 3.95 (1H), 4.06 (1H), 4.17 (1H), 5.70(1H), 6.64 (1H), 7.12 (1H), 7.25 (1H), 7.67 (1H), 8.59 (1H) ppm.

¹H-NMR (CDCl₃) of C: δ=1.01 (3H), 1.04 (3H), 1.20 (3H), 1.43 (3H), 1.68(3H), 1.12-1.93 (6H), 2.02-2.64 (5H), 2.13 (3H), 3.22 (1H), 3.38 (1H),3.69 (1H), 4.56 (1H), 5.11 (1H), 5.18 (1H), 6.28 (1H), 7.03 (1H), 7.21(1H), 7.37 (1H), 7.48 (1H), 8.29 (1H) ppm.

¹H-NMR (CDCl₃) of D: δ=1.01 (3H), 1.06 (3H), 1.18 (3H), 1.30 (3H), 1.46(3H), 1.13-1.89 (8H), 2.14 (3H), 2.09-2.30 (2H), 2.52 (1H), 2.78 (1H),3.17 (1H), 3.29 (1H), 3.71 (1H), 4.54 (1H), 5.37 (1H), 6.24 (1H), 6.96(1H), 7.22 (1H), 7.37 (1H), 7.42 (1H), 8.28 (1H) ppm.

¹H-NMR (CDCl₃) of E: δ=0.96 (3H), 1.06 (3H), 1.10 (3H), 1.29 (3H), 1.43(3H), 1.22-1.77 (6H), 1.78-2.18 (3H), 2.11 (3H), 2.35-2.52 (2H), 2.96(1H), 3.31 (1H), 3.43 (1H), 3.91 (1H), 4.49 (1H), 5.42 (1H), 5.49 (1H),7.02 (1H), 7.19 (1H), 7.33 (1H), 7.45 (11H), 8.28 (1H) ppm.

EXAMPLE 22(4S,7R,8S,9S,13(E),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dioneEXAMPLE 22a(3S,6R,7S,8S,12E,15,16E)-3,7-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-15-hydroxy-17-(2-pyridyl)-5-oxo-heptadeca-12,16-dienoicacid

Analogously to Example 1i, 370 mg (444 μmol) of compound A that ispresented according to Example 20h is reacted, and after working up andpurification, 309 mg (430 μmol, 97%) of the title compound is isolatedas a colorless oil.

EXAMPLE 22b(4S,7R,8S,9S,13(E),16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1aw, 309 g (430 μmol) of the compound that ispresented according to Example 22a is reacted, and after working up andpurification, 233 mg (333 μmol, 77%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.02-0.17 (12H), 0.88 (18H), 0.93 (3H), 1.09 (3H),1.12 (3H), 1.16-1.37 (2H), 1.19 (3H), 1.45-1.64 (3H), 1.59 (3H), 1.93(1H), 2.08-2.21 (1H), 2.18 (3H), 2.50 (1H), 2.54-2.70 (3H), 3.07 (1H),3.90 (1H), 4.51 (1H), 5.20 (1H), 5.30 (1H), 6.58 (1H), 7.10 (1H), 7.19(1H), 7.63 (1H), 8.60 (1H) ppm.

EXAMPLE 22(4S,7R,8S,9S,13(E),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 228 mg (326 μmol) of the compound that ispresented according to Example 22b is reacted, and after working-up andpurification, 131 mg (278 μmol, 85%) of the title compound is isolatedas a colorless oil

¹H-NMR (CDCl₃): δ=0.98 (3H), 1.07 (3H), 1.17 (3H), 1.31 (3H), 1.20-1.46(3H), 1.52-1.83 (2H), 1.61 (3H), 1.98 (1H), 2.08 (3H), 2.17 (1H), 2.39(1H), 2.41-2.66 (3H), 3.18-3.39 (2H), 3.66 (1H), 3.87 (1H), 4.38 (1H),5.14 (1H), 5.42 (1H), 6.60 (1H), 7.13 (1H), 7.32 (1H), 7.69 (1H), 8.56(1H) ppm.

EXAMPLE 23(1R,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclor[14.1.0]pentadecane-5,9-dione(A) and(1S,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)(1R,3S(E),7S,10R,11S,12S,16R)-7,11-dihydroxy-3-(1-methyl-2-(2-N-oxidopyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(C) and(1S,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-N-oxidopyridyl)ethenyl)-8,8,10,12,16-pentamethyl-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(D)

Analogously to Example 14, 50 mg (106 μmol) of the compound that ispresented according to Example 20 is reacted, and after working-up andpurification, 5.3 mg (11 μmol, 10%) of title compound A (or B), 4.4 mg(9 μmol, 9%) of title compound B (or A), 9.6 mg (10 μmol, 9%) of titlecompound C (or D), and 11.1 mg (11 μmol, 11%) of title compound D (or C)are isolated.

¹H-NMR (CDCl₃) of A or B: δ=0.94 (3H), 1.04 (3H), 1.13 (3H), 1.28 (3H),1.39 (3H), 2.11 (3H), 1.01-2.15 (9H), 2.44 (1H), 2.58 (1H), 2.74 (1H),2.91 (1H), 3.31 (1H), 3.73 (1H), 4.21 (1H), 4.30 (1H), 5.53 (1H), 6.53(1H), 7.13 (1H), 7.30 (1H), 7.67 (1H), 8.57 (1H) ppm.

¹H-NMR (CDCl₃) of B or A: δ=0.93 (3H), 1.09 (3H), 1.14 (3H), 1.28 (3H),1.37 (3H), 1.22-2.16 (9H), 2.09 (3H), 2.46 (1H), 2.57 (1H), 2.96 (1H),3.08 (1H), 3.26 (1H), 3.72 (1H), 3.89 (1H), 4.37 (1H), 5.47 (1H), 6.62(1H), 7.13 (1H), 7.28 (1H), 7.68 (1H), 8.57 (1H), ppm.

¹H-NMR (CDCl₃) of C or D: δ=0.93 (3H), 1.06 (3H), 1.19 (3H), 1.21 (3H),1.44 (3H), 1.15-2.01 (8H), 2.10 (3H), 2.12-2.26 (2H), 2.49 (1H), 2.89(1H), 3.26 (1H), 3.48 (1H), 3.67 (1H), 4.63 (1H), 5.45 (1H), 5.76 (1H),7.09 (1H), 7.21 (1H), 7.36 (1H), 7.45 (1H), 8.29 (1H) ppm.

¹H-NMR (CDCl₃) of D or C: δ=0.96 (3H), 1.06 (3H), 1.15 (3H), 1.24 (3H),1.43 (3H), 1.02-2.19 (9H), 2.08 (3H), 2.23 (1H), 2.56 (1H), 2.96 (1H),3.29 (1H), 3.68 (2H), 4.53 (1H), 5.60-5.72 (2H), 7.10 (1H), 7.21 (1H),7.37 (1H), 7.52 (1H), 8.29 (1H) ppm.

EXAMPLE 24(4S,7R,8S,9S,13(Z),16S(E))-4,8-Dihydroxy-7-ethyl-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dioneEXAMPLE 24h, Variant I(3S,6R,7S,8S,12E/Z,15S,16E)-6-Ethyl-1,3,7,15-tetrakis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-heptadeca-12,16-dien-5-oneEXAMPLE 24a/I (2S)-2-Methyl-1-(tetrahydropyran-2-yloxy)-heptan-6-one

Analogously to Example 1m, 9.0 g (39.1 mmol) of the compound that ispresented according to Example 1v is reacted, and after working-up andpurification, 8.05 g (35.3 mmol, 90%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.93 (3H), 1.12 (1H), 1.32-1.89 (10H), 2.14 (3H), 2.42(2H), 3.19 (1H), 3.45-3.63 (2H), 3.84 (1H), 4.56 (1H) ppm.

EXAMPLE 24b/I(2S,6E/Z,9S,10E)-9-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-11-(2-pyridyl)-1-(tetrahydropyran-2-yloxy)-2,6,10-trimethyl-undeca-6,10-diene

Analogously to Example 7ao or 20b, 1.89 g (8.28 mmol) of the compoundthat is presented according to Example 24a/I is reacted with 10.0 g(12.4 mmol) of the compound that is presented according to Example 20awith use of n-butyllithium as a base, and after working-up andpurification, 1.98 g (3.2 mmol, 38%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.81-0.92 (3H), 1.08 (9H), 1.18-1.92 (16H), 2.02 (3H),2.19-2.42 (2H), 3.02-3.62 (3H), 3.83 (1H), 4.20 (1H), 4.55 (1H), 5.00(1H), 6.24 (1H), 6.98-7.10 (2H), 7.22-7.46 (6H), 7.57 (1H), 7.62-7.75(4H), 8.58 (1H) ppm.

EXAMPLE 24c/I(2S,6E/Z,9S,10E)-11-(2-Pyridyl)-1-(tetrahydropyran-2-yloxy)-2,6,10-trimethyl-undeca-6,10-dien-9-ol

Analogously to Example 1i, 1.98 g (3.2 mmol) of the compound that ispresented according to Example 24b/I is reacted, and after working-upand purification, 1.16 g (3.0 mmol, 94%) of the title compound isisolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.87-1.00 (3H), 1.12 (1H), 1.32-1.95 (11H), 1.67+1.73(3H), 1.98-2.18 (2H), 2.10 (3H), 2.40 (2H), 3.08-3.28 (1H), 3.42-3.65(2H), 3.84 (1H), 4.19 (1H), 4.55 (1H), 5.19 (1H), 6.59 (1H), 7.10 (1H),7.24 (1H), 7.63 (1H), 8.60 (1H) ppm.

EXAMPLE 24d/I(2S,6E/Z,9S,10E)-9-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-11-(2-pyridyl)-1-(tetrahydropyran-2-yloxy)-2,6,10-trimethyl-undeca-6,10-diene

Analogously to Example 1n, 1.15 g (2.97 mmol) of the compound that ispresented according to Example 24c/I is reacted, and after working-upand purification, 1.43 g (2.85 mmol, 96%) of the title compound isisolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.03 (3H), 0.08 (3H), 0.81-0.98 (12H), 1.11 (1H),1.28-2.10 (12H), 1.60+1.69 (3H), 2.06 (3H), 2.28 (2H), 3.07-3.27 (1H),3.42-3.63 (2H), 3.85 (1H), 4.12 (1H), 4.56 (1H), 5.18 (1H), 6.48 (1H),7.08 (1H), 7.22 (1H), 7.62 (1H), 8.60 (1H) ppm.

EXAMPLE 24e/I(2S,6E/Z,9S,10E)-9-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-11-(2-pyridyl)-2,6,10-trimethyl-undeca-6,10-dien-1-ol

Analogously to Example 1f, 1.43 g (2.85 mmol) of the compound that ispresented according to Example 24d/I is reacted with use ofp-toluenesulfonic acid-monohydrate at 23° C., and after working-up andpurification, 1.11 g (2.66 mmol, 93%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.03 (3H), 0.08 (3H), 0.82-0.96 (12H), 0.97-1.71 (6H),1.59+1.69 (3H), 1.90-2.14 (2H), 2.04 (3H), 2.30 (2H), 3.35-3.56 (2H),4.13 (1H), 5.13+5.21 (1H), 6.48 (1H), 7.10 (1H), 7.25 (1H), 7.63 (1H),8.58 (1H) ppm.

EXAMPLE 24f/I(2S,6E/Z,9S,10E)-9-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-11-(2-pyridyl)-2,6,10-trimethyl-undeca-6,10-dienal

Analogously to Example 1k, 1.01 g (2.42 mmol) of the compound that ispresented according to Example 24e/I is reacted, and after working-upand purification, 921 mg (2.22 mmol, 92%) of the title compound isisolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.03 (3H), 0.08 (3H), 0.92 (9H), 1.05+1.09 (3H),1.22-1.75 (4H), 1.60+1.68 (3H), 1.95-2.11 (2H), 2.07 (3H), 2.23-2.38(3H), 4.12 (1H), 5.19 (1H), 6.48 (1H), 7.08 (1H), 7.22 (1H), 7.63 (1H),8.60 (1H), 9.57+9.61 (1H) ppm.

EXAMPLE 24g/I(3S,6R,7S,8S,12E/Z,15S,16E)-6-Ethyl-7-hydroxy-1,3,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-heptadeca-12,16-dien-5-one(A) and(3S,6S,7R,8S,12E/Z,15S,16E)-6-ethyl-7-hydroxy-1,3,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-heptadeca-12,16-dien-5-one(B)

Analogously to Example 1ak, 1.0 g (2.41 mmol) of the compound that ispresented according to Example 24f/I is reacted with 1.16 g (2.78 mmol)of the compound that is presented according to Example 1m, and afterworking-up and purification, 972 mg (1.17 mmol, 48%) of title compound Aand 178 mg (0.21 mmol, 9%) of title compound B are isolated in each caseas a colorless oil.

¹H-NMR (CDCl₃) of A: δ=0.00-0.14 (18H), 0.80-0.95 (33H), 1.00-1.81 (9H),1.11 (3H), 1.17 (3H), 1.60+1.68 (3H), 1.90-2.11 (2H), 2.04 (3H), 2.29(2H), 3.03 (1H), 3.18 (1H), 3.32 (1H), 3.54-3.77 (2H), 3.99 (1H), 4.12(1H), 5.18 (1H), 6.48 (1H), 7.09 (1H), 7.23 (1H), 7.62 (1H), 8.60 (1H)ppm.

¹H-NMR (CDCl₃) of B: δ=−0.02-0.14 (18H), 0.83-1.01 (33H), 1.02-1.80(9H), 1.10 (3H), 1.16 (3H), 1.62+1.70 (3H), 1.92-2.10 (2H), 2.06 (3H),2.30 (2H), 3.02 (1H), 3.15 (1H), 3.42 (1H), 3.53-3.74 (2H), 4.02 (1H),4.12 (1H), 5.19 (1H), 6.49 (1H), 7.09 (1H), 7.23 (1H), 7.63 (1H), 8.60(1H) ppm.

EXAMPLE 24h/I(3S,6R,7S,8S,12E/Z,15S,16E)-6-Ethyl-1,3,7,15-tetrakis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-heptadeca-12,16-dien-5-one

Analogously to Example 1aq, 972 mg (1.17 mmol) of compound A that ispresented according to Example 24g/I is reacted, and after working-upand purification, 1.02 g (1.08 mmol, 92%) of the title compound isisolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.00-0.12 (24H), 0.78-0.97 (42H), 1.00-1.80 (9H), 1.03(3H), 0.21 (3H), 1.60+1.68 (3H), 1.90-2.10 (2H), 2.05 (3H), 2.28 (2H),3.02 (1H), 3.52-3.73 (2H), 3.82 (1H), 3.91 (1H), 4.11 (1H), 5.19 (1H),6.49 (1H), 7.08 (1H), 7.22 (1H), 7.61 (1H), 8.60 (1H) ppm.

EXAMPLE 24h, Variant II(3S,6R,7S,8S,12E/Z,15S,16E)-6-Ethyl-1,3,7,15-tetrakis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-heptadeca-12,16-dien-5-oneEXAMPLE 24a/II(4S(4R,5S,6S,10E/Z,13S,14E))-4-(13-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-ethyl-15-(2-pyridyl)-3-oxo-5-(tetrahydropyran-2-yloxy)-2,6,10,14-tetramethyl-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1ao or 20b, 724 mg (1.59 mmol) of the compoundthat is presented according to Example 1an is reacted with 1.93 g (2.40mmol) of the compound that is presented according to Example 20a withuse of n-butyllithium as a base, and after working-up and purification,478 mg (0.56 mmol, 35%) of the title compound is isolated as a colorlessoil.

¹H-NMR (CDCl₃): δ=0.72-1.96 (48H), 2.01 (3H), 2.16-2.41 (2H), 3.03+3.13(1H), 3.41 (1H), 3.59-4.04 (3H), 4.12-4.32 (2H), 4.43+4.52 (1H), 5.01(1H), 6.23 (1H), 6.97-7.10 (2H), 7.21-7.46 (6H), 7.58 (1H), 7.62-7.74(4H), 8.57 (1H) ppm.

EXAMPLE 24b/II(4S(4R,5S,6S,10E/Z,13S,14E))-4-(4-Ethyl-13-hydroxy-15-(2-pyridyl)-3-oxo-5-(tetrahydropyran-2-yloxy)-2,6,10,14-tetramethyl-pentadeca-10,14-dien-2-yl)-2,2-dimethyl-[1,3]dioxane

Analogously to Example 1i, 660 mg (0.77 mmol) of the compound that ispresented according to Example 24a/II is reacted, and after working-upand purification, 475 mg (0.77 mmol, 100%) of the title compound isisolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.72-2.12 (39H), 2.09 (3H), 2.39 (2H), 3.07+3.17 (1H),3.42 (1H), 3.62-4.32 (6H), 4.43+4.54 (1H), 5.20 (1H), 6.61 (1H), 7.10(11H), 7.25 (1H), 7.63 (1H), 8.60 (1H) ppm.

EXAMPLE 24c/II(3S,6R,7S,8S,12E/Z,15S,16E)-6-Ethyl-1,3,7,15-tetrahydroxy-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-heptadeca-12,16-dien-5-one

Analogously to Example 1f, 472 mg (0.77 mmol) of the compound that ispresented according to Example 24b/II is reacted with use ofp-toluenesulfonic acid-monohydrate at 23° C., and after working-up andpurification, 348 mg (0.71 mmol, 92%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.75-0.92 (6H), 1.07 (3H), 1.11-2.47 (13H), 1.26 (3H),1.63 (3H), 1.72 (3H), 2.04+2.05 (3H), 2.96 (1H), 3.18 (1H), 3.41+3.48(1H), 3.86 (2H), 4.04-4.23 (2H), 5.18+5.23 (1H), 6.57 (1H), 7.12 (1H),7.29 (1H), 7.67 (1H), 8.59 (1H) ppm.

EXAMPLE 24h/II(3S,6R,7S,8S,12E/Z,15S,16E)-6-Ethyl-1,3,7,15-tetrakis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-heptadeca-12,16-dien-5-one

Analogously to Example 1aq, 343 mg (0.70 mmol) of the compound that ispresented according to Example 24c/II is reacted, and after working-upand purification, 497 mg (0.52 mmol, 75%) of the title compound isisolated as a colorless oil.

¹H-NMR (CDCl₃): coverage is identical to that described under Example24h/I.

EXAMPLE 24i(3S,6R,7S,8S,12E/Z,15S,16E)-6-Ethyl-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]-oxy]-4,4,8,12,16-pentamethyl-1-hydroxy-17-(2-pyridyl)-heptadeca-12,16-dien-5-one

Analogously to Example 1ar, 1.71 g (1.81 mmol) of the compound that ispresented according to Example 24h/I or Example 24h/II is reacted, andafter working-up and purification, 1.38 g (1.66 mmol, 97%) of the titlecompound is isolated as a colorless oil.

¹H-NMR (CDCl₃): δ=0.00-0.15 (18H), 0.80-0.98 (33H), 1.02-2.10 (1H), 1.09(3H), 1.21 (3H), 1.59+1.68 (3H), 2.05 (3H), 2.29 (2H), 3.01 (1H), 3.69(2H), 3.84 (1H), 4.02-4.19 (3H), 5.18 (1H), 6.48 (1H), 7.09 (1H), 7.22(1H), 7.62 (1H), 8.59 (1H) ppm.

EXAMPLE 24k(3S,6R,7S,8S,12E/Z,15S,16E)-6-Ethyl-3,7,15-tris-[[dimethyl(1,1-dimethlethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-5-oxo-heptadeca-12,16-dienal

Analogously to Example 1k, 1.38 g (1.66 mmol) of the compound that ispresented according to Example 24i is reacted, and after working-up andpurification, 1.34 g (1.61 mmol, 97%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.01-0.13 (18H), 0.78-0.97 (35H), 1.09 (3H), 1.13-1.79(5H), 1.21 (3H), 1.60+1.68 (3H), 1.91-2.10 (2H), 2.05 (3H), 2.28 (2H),2.40 (1H), 2.57 (1H), 3.02 (1H), 3.82 (1H), 4.12 (1H), 4.48 (1H), 5.18(1H), 6.48 (1H), 7.08 (1H), 7.22 (1H), 7.62 (1H), 8.60 (1H), 9.79 (1H)ppm.

EXAMPLE 24l(3S,6R,7S,8S,12E,15S,16E)-6-Ethyl-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-5-oxo-heptadeca-12,16-dienoicacid (A) and(3S,6R,7S,8S,12Z,15S,16E)-6-ethyl-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,8,12,16-pentamethyl-17-(2-pyridyl)-5-oxo-heptadeca-12,16-dienoicacid (B)

Analogously to Example 1at, 1.34 g (1.61 mmol) of the compound that ispresented according to Example 24k is reacted, and after working-up andpurification, 433 mg (0.51 mmol, 32%) of title compound A and 662 mg(0.78 mmol, 49%) of title compound B are isolated in each case as acolorless oil.

¹H-NMR (CDCl₃) of A: δ=0.00-0.16 (18H), 0.78-0.93 (35H), 0.98-1.71 (6H),1.12 (3H), 1.21 (3H), 1.56 (3H), 1.80-2.07 (2H), 1.93 (3H), 2.23-2.41(3H), 2.67 (1H), 3.05 (1H), 3.86 (1H), 4.12 (1H), 4.33 (1H), 5.11 (1H),6.48 (1H), 7.24 (1H), 7.33 (1H), 7.69 (1H), 8.61 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=−0.01-0.17 (18H), 0.81-0.96 (35H), 1.00-1.78(6H), 1.15 (3H), 1.21 (3H), 1.70 (3H), 1.89 (1H), 1.96 (3H), 2.11-2.42(4H), 2.59 (1H), 3.00 (1H), 3.82 (1H), 4.17 (1H), 4.41 (1H), 5.24 (1H),6.63 (1H), 7.19 (1H), 7.33 (1H), 7.71 (1H), 8.64 (1H) ppm.

EXAMPLE 24m(3S,6R,7S,8S,12Z,15S,16E)-3,7-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-6-ethyl-4,4,8,12,16-pentamethyl-15-hydroxy-17-(2-pyridyl)-5-oxo-heptadeca-12,16-dienoicAcid

Analogously to Example 1i, 662 mg (0.78 mmol) of compound B that ispresented according to Example 24 l is reacted at 23° C., and afterworking-up, 680 mg of the title compound is isolated as a crude product,which is further reacted without purification.

EXAMPLE 24n(4S,7R,8S,9S,13(Z),16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-methyl-2-(2-pyridyl)ethenyl)-7-ethyl-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1aw, 680 mg (max. 0.78 mmol) of the compound thatis presented according to Example 24m is reacted, and after working-upand purification, 287 mg (402 μmol, 52%) of the title compound isisolated as a colorless oil.

¹H-NMR (CDCl₃): δ=−0.11 (3H), 0.03-0.15 (9H), 0.72 (3H), 0.80-1.78(23H), 0.83 (3H), 0.92 (3H), 0.98 (3H), 1.11 (3H), 1.18 (3H), 1.68 (3H),1.85 (1H), 2.09 (1H), 2.12 (3H), 2.46 (1H), 2.55-2.82 (3H), 3.05 (1H),4.01 (1H), 4.03 (1H), 4.99 (1H), 5.16 (1H), 6.54 (1H), 7.08 (1H), 7.23(1H), 7.61 (1H), 8.58 (1H) ppm.

EXAMPLE 24(4S,7R,8S,9S,13(Z),16S(E))-4,8-Dihydroxy-7-ethyl-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 282 mg (395 μmol) of the compound that ispresented according to Example 24n is reacted, and after working-up andpurification, 115 mg (237 μmol, 60%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.89 (3H), 1.04 (3H), 1.09 (3H), 1.22-2.11 (8H), 1.36(3H), 1.70 (3H), 2.07 (3H), 2.20-2.39 (3H), 2.49 (1H), 2.65 (1H), 2.69(1H), 3.23 (1H), 3.70 (1H), 4.35 (1H), 4.59 (1H), 5.12 (1H), 5.19 (1H),6.61 (1H), 7.13 (1H), 7.29 (1H), 7.69 (1H), 8.53 (1H) ppm.

EXAMPLE 25(1S,3S(E),7S,10R11S,12S,16R)-7,11-Dihydroxy-10-ethyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-10-ethyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(B) and(4S,7R,8S,9S,13(Z),16S(E))-4,8-dihydroxy-9-ethyl-16-(1-methyl-2-(2-N-oxypyridyl)ethenyl)-1-oxa-5,5,7,13-tetramethyl-cyclohexadec-13-ene-2,6-dione(C) and(1S,3S(E),7S,10R,11S,12S,16R)-7,11-dihydroxy-10-ethyl-3-(1-methyl-2-(2-N-oxypyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(D) and(1R,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-10-ethyl-3-(1-methyl-2-(2-N-oxypyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(E)

Analogously to Example 14, 50 mg (103 μmol) of the compound that ispresented according to Example 24 is reacted, and after working-up andpurification, 15.3 mg (30 μmol, 30%) of title compound A, 2 mg (4 μmol,4%) of title compound B, 2 mg (4 μmol, 4%) of title compound C, 21 mg(42 μmol, 41%) of title compound D and 3.3 mg (7 μmol, 6%) of titlecompound E are isolated in each case as a colorless solid.

¹H-NMR (CDCl₃) of A: δ=0.87 (3H), 0.99 (3H), 1.06 (3H), 1.21-2.03 (10H),1.30 (3H), 1.39 (3H), 2.03 (3H), 2.15 (1H), 2.37 (1H), 2.56 (1H), 2.81(1H), 2.83 (1H), 3.32 (1H), 3.66 (1H), 4.36 (1H), 5.24 (1H), 5.45 (1H),6.61 (1H), 7.16 (1H), 7.29 (1H), 7.70 (1H), 8.53 (1H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.85 (3H), 0.95 (3H), 1.04 (3H), 1.20-1.93 (10H),1.30 (3H), 1.38 (3H), 2.08 (1H), 2.11 (3H), 2.42-2.61 (2H), 2.95 (1H),2.98 (1H), 3.22 (1H), 3.63 (1H), 3.93 (1H), 4.33 (1H), 5.59 (1H), 6.66(1H), 7.13 (1H), 7.28 (1H), 7.67 (1H), 8.58 (1H) ppm.

¹H-NMR (CDCl₃) of C: δ=0.80-1.92 (8H), 0.92 (3H), 1.03 (3H), 1.08 (3H),1.44 (3H), 1.70 (3H), 2.08-2.64 (5H), 2.12 (3H), 2.82 (1H), 3.29 (1H),3.67 (1H), 4.53 (1H), 5.09 (1H), 5.17 (1H), 6.19 (1H), 6.99 (1H), 7.19(1H), 7.35 (1H), 7.44 (1H), 8.29 (1H) ppm.

¹H-NMR (CDCl₃) of D: δ=0.87 (3H), 1.00 (3H), 1.04 (3H), 1.09-2.03 (10H),1.29 (3H), 1.42 (3H), 2.10 (3H), 2.18-2.32 (2H), 2.53 (1H), 2.67-2.82(2H), 3.31 (1H), 3.62 (1H), 4.52 (1H), 5.41 (1H), 6.16 (1H), 6.93 (1H),7.21 (1H), 7.37 (1H), 7.42 (1H), 8.28 (1H) ppm.

¹H-NMR (CDCl₃) of E: δ=0.83 (3H), 0.94 (3H), 1.08 (3H), 1.20-2.08 (11H),1.29 (3H), 1.45 (3H), 2.12 (3H), 2.39-2.56 (2H), 2.87 (1H), 3.24 (1H),3.29 (1H), 3.87 (1H), 4.52 (1H), 5.41 (1H), 5.56 (1H), 7.03 (1H), 7.19(1H), 7.34 (1H), 7.46 (1H), 8.29 (1H) ppm.

EXAMPLE 26(4S,7R,8S,9S,13(E),16S(E))-4,8-Dihydroxy-7-ethyl-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,7,13-tetramethyl-cyclohexadec-13-ene-2,6-dioneEXAMPLE 26a(3S,6R,7S,8S,12E,15S,16E)-3,7-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-6-ethyl-4,4,8,12,16-pentamethyl-15-hydroxy-17-(2-pyridyl)-5-oxo-heptadeca-12,16-dienoicAcid

Analogously to Example 1i, 433 mg (0.51 mmol) of compound A that ispresented according to Example 24l is reacted, and after working-up, 447mg of the title compound is isolated as a crude product, which isfurther reacted without purification.

EXAMPLE 26b(4S,7R,8S,9S,13(E),16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-7-ethyl-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1aw, 447 mg (511 μmol) of the compound that ispresented according to Example 26a is reacted, and after working-up andpurification, 264 mg (370 μmol, 72%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.06-0.15 (12H), 0.85 (3H), 0.89 (9H), 0.91 (9H), 0.94(3H), 1.08-1.92 (11H), 1.12 (3H), 1.21 (3H), 2.10-2.23 (1H), 2.16 (3H),2.40 (1H), 2.46-2.68 (3H), 2.98 (1H), 3.95 (1H), 4.41 (1H), 5.23 (1H),5.30 (1H), 6.57 (1H), 7.10 (1H), 7.21 (1H), 7.63 (1H), 8.60 (1H) ppm.

EXAMPLE 26(4S,7R,8S,9S,13(E),16S(E))-4,8-Dihydroxy-7-ethyl-16-(1-methyl-2-(2-pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 260 mg (364 μmol) of the compound that ispresented according to Example 26b is reacted, and after working-up andpurification, 121 mg (249 μmol, 68%) of the title compound is isolatedas a colorless oil.

¹H-NMR (CDCl₃): δ=0.83 (3H), 0.90 (1H), 0.98 (3H), 1.01 (3H), 1.31 (3H),1.37-2.00 (7H), 1.61 (3H), 2.08 (3H), 2.18 (1H), 2.37-2.52 (3H), 2.60(1H), 3.35 (1H), 3.70 (1H), 3.83-4.32 (2H), 4.45 (1H), 5.08 (1H), 5.39(1H), 6.58 (1H), 7.13 (1H), 7.35 (1H), 7.68 (1H), 8.53 (1H) ppm.

EXAMPLE 27(1R,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1S,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-10-ethyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)(1R,3S(E),7S,10R,11S,12S,16R)-7,11-dihydroxy-10-ethyl-3-(1-methyl-2-(2-N-oxidopyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclor[14.1.0]heptadecane-5,9-dione(C) and(1S,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-10-ethyl-3-(1-methyl-2-(2-N-oxidopyridyl)ethenyl)-8,8,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(D)

Analogously to Example 14, 59 mg (121 μmol) of the compound that ispresented according to Example 26 is reacted, and after working-up andpurification, 5 mg (10 μmol, 8%) of title compound A or B, 2 mg (4 μmol,3%) of title compound B or A, 14 mg (27 μmol, 22%) of title compound Cor D and 6.9 mg (13 μmol, 11%) of title compound D or C are isolated ineach case as a colorless solid.

¹H-NMR (CDCl₃) of A or B: δ=0.83 (3H), 0.92 (3H), 1.02 (3H), 1.09-2.19(12H), 1.27 (3H), 1.37 (3H), 2.11 (3H), 2.43-2.61 (2H), 2.88 (1H), 3.31(1H), 3.78 (1H), 4.26 (1H), 4.33 (1H), 5.48 (1H), 6.64 (1H), 7.12 (1H),7.30 (1H), 7.67 (1H), 8.57 (1H) ppm.

¹H-NMR (CDCl₃) of B or A: δ=0.86 (3H), 0.93 (3H), 1.09 (3H), 1.19-2.19(11H), 1.27 (3H), 1.38 (3H), 2.10 (3H), 2.50-2.63 (2H), 2.87 (1H), 2.98(1H), 3.28 (1H), 3.71 (1H), 3.88 (1H), 4.31 (1H), 5.48 (1H), 6.62 (1H),7.13 (1H), 7.28 (1H), 7.67 (1H), 8.85 (1H) ppm.

¹H-NMR (CDCl₃) of C or D: δ=0.84 (3H), 0.91 (3H), 1.06 (3H), 1.11-2.08(10H), 1.26 (3H), 1.38 (3H), 2.02 (3H), 2.19 (1H), 2.37 (1H), 2.53 (1H),2.92 (1H), 3.34 (1H), 3.56-3.72 (2H), 4.53 (1H), 5.05 (1H), 5.60 (1H),6.99 (1H), 7.21 (1H), 7.33 (1H), 7.45 (1H), 8.28 (1H) ppm.

¹H-NMR (CDCl₃) of D or C: δ=0.84 (3H), 0.89 (3H), 1.07 (3H), 1.15-2.23(11H), 1.22 (3H), 1.43 (3H), 2.09 (3H), 2.36 (1H), 2.53 (1H), 2.97 (1H),3.02 (1H), 3.32 (1H), 3.58 (1H), 4.58 (1H), 5.44 (1H), 5.58 (1H), 7.06(1H), 7.21 (1H), 7.36 (1H), 7.44 (1H), 8.29 (1H) ppm.

EXAMPLE 28(4S,7R,8S,9S,13(Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-7,9,13-trimethyl-5,5-trimethylene-cyclohexadec-13-ene-2,6-dioneEXAMPLE 28a 1,1-Cyclobutanedimethanol

170 ml of a 1.2 molar solution of dilsobutylaluminum hydride is added indrops to a solution of 20 g (99.9 mmol) of 1,1-cyclobutanedicarboxylicacid diethyl ester in 200 ml of absolute tetrahydrofuran at 0° C. It isallowed to stir for one more hour at 0° C., and then 30 ml of water isadded. It is filtered on Celite. The filtrate is dried with sodiumsulfate and concentrated by evaporation in a vacuum. The crude productthat is obtained (9.9 g, 85.2 mmol, 85%) is used without purification inthe next step.

EXAMPLE 28b1-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]-cyclobutanemethanol

A solution of 9.9 g (85 mmol) of the compound, presented according toExample 28a, in 100 ml of absolute tetrahydrofuran is added to asuspension of 3.4 g of sodium hydride (60% in oil) in 35 ml of absolutetetrahydrofuran at 0° C. It is allowed to stir for 30 more minutes, andthen a solution of 12.8 g of tert-butyldimethylsilyl chloride in 50 mlof tetrahydrofuran is added. It is allowed to stir for one more hour at25° C., and then the reaction mixture is poured onto saturated aqueoussodium bicarbonate solution. It is extracted with ethyl acetate. Theorganic phase is washed with saturated sodium chloride solution anddried on sodium sulfate. After the solvent is drawn off in a vacuum, thecrude product that is obtained is purified by column chromatography onsilica gel with a mixture of hexane/ethyl acetate. 13.5 g (58.6 mmol,69%) of the title compound is obtained.

¹H-NMR (CDCl₃): δ=0.04 (6H), 0.90 (9H), 1.70-2.00 (6H), 3.70 (4H) ppm

EXAMPLE 28c1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]-cyclobutanecarbaldehyde

Analogously to Example 1k, after purification, 7.7 g (33.7 mmol, 58%) ofthe title compound is obtained from 13.5 g (58.6 mmol) of the compoundthat is described under 28b.

¹H-NMR (CDCl₃): δ=9.70 s ((1H), 3.83 s (2H), 2.20-2.30 m (2H), 1.85-2.00m (4H), 0.90 s (9H), 0.03 s (6H) ppm.

EXAMPLE 28d [1R-[1α(R*)2β]]-2-Phenylcyclohexyl3-[1-[[[dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutyl]-3-hydroxypropanoate(A) and [1R-[1α(S*),2β]]-2-phenylcyclohexyl3-[1-[[[dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutyl]-3-hydroxypropanoate(B)

Lithium diisopropylamide in absolute tetrahydrofuran is produced from7.2 ml of diisopropylamine and butyllithium (32 ml of a 1.6 molarsolution in hexane). Then, a solution of 11.2 g(1R-trans)-2-phenylcyclohexyl acetate in 100 ml of absolutetetrahydrofuran is added at −78° C., and it is allowed to stir for 30more minutes at this temperature. Then, a solution of 7.7 g (33.7 mmol)of the compound, presented according to Example 28c, in 50 ml oftetrahydrofuran is added. It is allowed to stir for 1.5 more hours at−78° C., and then the reaction mixture is poured onto saturated aqueousammonium chloride solution. It is extracted with ethyl acetate, theorganic phase is washed with saturated sodium chloride solution, driedon sodium sulfate and concentrated by evaporation in a vacuum. Aftercolumn chromatography of the crude product on silica gel with a mixtureof hexane/ethyl acetate, 6.34 g (14.2 mmol, 42%) of title compound A and4.22 g (9.4 mmol, 28%) of title compound B are obtained.

¹H-NMR (CDCl₃) of A: δ=0.04 (6H), 0.98 (9H), 2.69 (1H), 3.08 (1H), 3.60(1H), 3.67 (1H), 3.78-3.84 (1H), 4.97 (1H), 7.15-7.30 (5H) ppm.

¹H-NMR (CDCl₃) of B: δ=0.03 (6H), 0.90 (9H), 2.68 (1H), 2.80 (1H), 3.56(2H), 3.68-3.72 (1H), 4.99 (1H), 7.18-7.30 m (5H) ppm.

EXAMPLE 28e(S)-1-[1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]-cyclobutyl]-1,3-propanediol

4 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene isadded in drops to a solution of 1 g (2.24 mmol) of compound A, presentedaccording to Example 28d, in 10 ml of absolute toluene at 0° C. It isallowed to stir for 1.5 more hours at 0° C., and then 5 ml of water isadded. It is filtered on Celite. The filtrate is dried on sodium sulfateand concentrated by evaporation in a vacuum. After column chromatographyof the crude product on silica gel with a mixture of hexane/ethylacetate, 370 mg (1.35 mmol, 60%) of the title compound is obtained.

¹H-NMR (CDCl₃): δ=0.05 (6H), 0.90 (9H), 1.55-1.60 (2H), 1.80 (2H), 1.90(3H), 2.10 (1H), 3.75 (1H), 3.85-3.95 (4H) ppm.

EXAMPLE 28f(S)-2,2-Dimethyl-4-[1-[[[dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobutyl]-1,3-dioxane

Analogously to Example 1h, after purification, 338 mg (1.07 mmol, 79%)of the title compound is obtained from 370 mg (1.35 mmol) of thecompound that is described under 28e.

¹H-NMR (CDCl₃): δ=0.03 (6H), 0.88 (9H), 1.38 (3H), 1.42 (3H), 1.50-1.80(4H), 2.00 (1H), 3.52 (1H), 3.62 (1H), 3.85-4.00 (3H) ppm.

EXAMPLE 28g (S)-1-(2,2-Dimethyl-1,3-dioxan-4-yl)cyclobutanemethanol

Analogously to 1i, 1.27 g (4.04 mmol) of the compound that is producedaccording to Example 28f is reacted with 6 ml of a 1 molar solution oftetrabutylammonium chloride in tetrahydrofuran. After columnchromatography, 794 mg (98%) of the title compound is obtained.

¹H-NMR (CDCl₃): δ=1.38 (3H), 1.46 (3H), 1.55-1.67 (2H), 1.75-2.05 (6H),2.97 (1H), 3.62 (1H), 3.84-4.10 (4H) ppm.

EXAMPLE 28h (S)-1-(2,2-Dimethyl-1,3-dioxan-4-yl)cyclobutanecarbaldehyde

Analogously to Example 1k, 794 mg (3.97 mmol) of 28g is reacted, and 786mg (100%) of the title compound is isolated as a crude product, which isused without purification in the next step.

EXAMPLE 28i(S)-1-(2,2-Dimethyl-1,3-dioxan-4-yl)-α-ethylcyclobutanemethanol

Analogously to Example 1l, 786 mg (3.97 mmol) of the compound that isdescribed under 28h is reacted with a 2 molar solution of ethylmagnesiumchloride in tetrahydrofuran. After purification, 835 mg (95%) of thetitle compound is obtained.

¹H-NMR (CDCl₃): δ=1.05 (3H), 1.38 (3H), 1.49 (3H), 1.60-2.10 (8H), 2.60(1H), 2.83 (1H), 3.50 (1H), 3.85-4.15 (3H) ppm.

EXAMPLE 28k(S)-1-[1-(2,2-Dimethyl-1,3-dioxan-4-yl)cyclobutyl]propan-1-one

Analogously to Example 1m, after purification, 689 mg (83%) of the titlecompound is obtained from 835 mg (3.67 mmol) of the compound that isdescribed under 28i.

¹H-NMR (CDCl₃): δ=1.03 (3H), 1.35 (1H), 1.36 (3H), 1.45 (3H), 1.55 (1H),1.65-1.90 (2H), 2.02 (1H), 2.14-2.30 (2H), 2.33 (1H), 2.45-2.60 (2H),3.80-4.00 (2H), 4.10 (1H) ppm.

EXAMPLE 28l (S)-1-[1-(1,3-Dihydroxypropyl)cyclobutyl]propan-1-one

680 mg (3 mmol) of the compound that is described under 28k is dissolvedin 30 ml of tetrahydrofuran. 1 ml of water and 30 mg ofp-toluenesulfonic acid are added, and it is allowed to stir for 30 moreminutes at 50° C. After working-up and purification, 471 mg (84%) of thetitle compound is obtained.

¹H-NMR (CDCl₃): δ=1.05 (3H), 1.10 (1H), 1.53 (1H), 1.65 (1H), 1.80-2.00(3H), 2.15 (1H), 2.40-2.70 (3H), 3.35 (1H), 3.55 (1H), 3.88 (1H), 4.10(1H) ppm.

EXAMPLE 28m(S)-1-(1,3-Bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]cyclobutyl)propan-1-one

Analogously to Example 1aq, after purification, 709 mg (68%) of thetitle compound is obtained from 470 mg (2.54 mmol) of the compound thatis described under 281.

¹H-NMR (CDCl₃): δ=0.02 (6H), 0.15 (3H), 0.17 (3H), 0.90 (9H), 0.94 (9H),1.05 (3H), 1.30-1.53 (2H), 1.70-1.85 (2H), 1.98 (1H), 2.23 (3H),2.45-2.53 (2H), 3.54 (2H), 4.11 (1H) ppm.

EXAMPLE 28n(2S,6E/Z,9S,10E)-9-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-11-(2-methylthiazol-4-yl)-1-(tetrahydropyran-2-yloxy)-2,6,10-trimethyl-undeca-6,10-diene

Analogously to Example 24b/I, after purification, 3.01 g (47%) of thetitle compound is obtained from 2.24 g (9.84 mmol) of the compound thatis described under 24 a/I, and 12.2 g (14.81 mmol) of the compound thatis described under 1ai, with use of butyllithium as a base.

¹H-NMR (CDCl₃): δ=0.86 (3H), 1.04 (9H), 1.55+1.60 (3H), 1.30 (2H), 1.99(3H), 2.25 (2H), 2.70 (3H), 1.10-3.20 (1H), 3.45-3.60 (2H), 3.86 (1H),4.14 (1H), 4.54 (1H), 4.97 (1H), 6.22 (1H), 6.78 (1H), 7.30-7.50 (6H),7.60-7.70 (4H) ppm.

EXAMPLE 28o(28,6E/Z,9S,10E)-11-(2-Methylthiazolyl-4-yl)-1-(tetrahydropyran-2-yloxy)-2,6,10-trimethyl-undeca-6,10-dien-9-ol

Analogously to Example 1i, after purification, 4.53 g (94%) of the titlecompound is obtained from 7.65 g (11.84 mmol) of the compound that isdescribed under 28n.

¹H-NMR (CDCl₃): δ=0.91 (3H), 1.10 (1H), 1.65+1.71 (3H), 2.04 (3H), 2.39(2H), 2.70 (3H), 3.12+3.21 (1H), 3.50+3.58 (2H), 3.85 (1H), 4.14 (1H),4.55 (1H), 5.15 (1H), 6.56 (1H), 6.93 (1H) ppm.

EXAMPLE 28p(2S,6E/Z,9S,10E)-9-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-11-(2-methylthiazol-4-yl)-1-(tetrahydropyran-2-yloxy)-2,6,10-trimethyl-undeca-6,10-diene

Analogously to Example 1ad, after purification, 5.68 g (98%) of thetitle compound is obtained from 4.53 g of the compound that is describedunder 28o.

¹H-NMR (CDCl₃): δ=0.00 (3H), 0.03 (3H), 0.90 (12H), 1.56+1.64 (3H), 1.99(3H), 2.21 (2H), 3.10+3.20 (1H), 3.45-3.60 (2H), 3.85 (1H), 4.10 (1H),4.57 (1H), 5.12 (1H), 6.45 (1H), 6.90 (1H) ppm.

EXAMPLE 28q(2S,6E/Z,9S,10E)-9-[[Dimethyl(1,1-dimethylethyl)silyl]Oxy]-11-(2-methylthiazol-4-1)-2,6,10-trimethyl-undeca-6,10-dien-1-ol

Analogously to Example 1f, after purification, 4.02 g (84%) of the titlecompound is obtained (2 hours of reaction time at 50° C.) from 5.68 g(10.88 mmol) of the compound that is described under 28p.

¹H-NMR (CDCl₃): δ=0.00 (3H), 0.05 (3H), 0.90 (12H), 1.60+1.65 (3H), 2.00(3H), 2.23 (2H), 2.71 (3H), 3.38-3.55 (2H), 4.10 (1H), 5.09+5.14 (1H),6.45+6.48 (1H), 6.91+6.93 (1H) ppm.

EXAMPLE 28r(2S,6E/Z,9S,10E)-9-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-11-(2-methylthiazol-4-yl)-2,6,10-trimethyl-undeca-6,10-dien-1-al

Analogously to Example 1k, after filtration on silica gel, 648 mg (98%)of the title compound is obtained from 667 mg (1.5 mmol) of the compoundthat is described under 28q.

¹H-NMR (CDCl₃): δ=0.01 (3H), 0.06 (3H), 0.90 (9H), 1.06+1.09 (3H),1.58+1.66 (3H), 2.00 (3H), 4.10 (1H), 5.13 (1H), 6.46 (1H), 6.91+6.93(1H) ppm.

EXAMPLE 28s(3S,6R,7S,8S,12Z,15S,16E)-7-Hydroxy-1,3,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-6,8,12,16-tetramethyl-4,4-trimethylene-17-(2-methylthiazol-4-yl)-heptadeca-12,16-dien-5-one(A) and(3S,6R,7S,8S,12E,15S,16E)-7-hydroxy-1,3,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-6,8,12,16-tetramethyl-4,4-trimethylene-17-(2-methylthiazol-4-yl)-heptadeca-12,16-dien-5-one(B)

Analogously to Example 1ak, after purification, 352 mg (27%) of titlecompound A and 227 mg (17%) of title compound B are obtained from 709 mg(1.71 mmol) of the compound that is described under 28 m and 667 mg(1.52 mmol) of the compound that is described under 28r.

¹H-NMR (CDCl₃) of compound A: δ=0.00 (3H), 0.04 (9H), 0.14 (3H), 0.16(3H), 0.80 (3H), 0.88 (18H), 0.91 (9H), 1.03 (3H), 1.68 (3H), 2.00 (3H),2.20-2.40 (3H), 2.72 (3H), 3.25 (1H), 3.44 (1H), 3.58 (3H), 4.10 (2H),5.13 (1H), 6.42 (1H), 6.93 (1H) ppm.

¹H-NMR (CDCl₃) of compound B: δ=0.00 (3H), 0.04 (6H), 0.08 (3H), 0.15(3H), 0.18 (3H), 0.80 (3H), 0.89 (18H), 0.92 (9H), 1.05 (3H), 1.60 (3H),2.00 (3H), 2.20-2.40 (3H), 2.70 (3H), 3.25 (1H), 3.45 (1H), 3.60 (3H),4.10 (2H), 5.15 (1H), 6.45 (1H), 6.91 (1H) ppm.

EXAMPLE 28t(3S,6R,7S,8S,12Z,15S,16E)-1,3,7,15-Tetrakis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-6,8,12,16-tetramethyl-4,4-trimethylene-17-(2-methylthiazol-4-yl)-heptadeca-12,16-dien-5-one

Analogously to Example 1aq, 381 mg (95%) of the title compound isobtained from 352 mg (0.41 mmol) of compound A that is described under28s.

¹H-NMR (CDCl₃): δ=0.00 (3H), 0.02 (6H), 0.04 (3H), 0.07 (3H), 0.09 (3H),0.13 (3H), 0.16 (3H), 0.90 (18H), 0.94 (18H), 0.95 (3H), 1.09 (3H), 1.68(3H), 2.20-2.40 (3H), 2.71 (3H), 3.10 (1H), 3.58 (2H), 3.78 (1H), 4.10(2H), 5.13 (1H), 6.47 (1H), 6.90 (1H) ppm.

EXAMPLE 28u(3S,6R,7-S,8S,12Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-1-hydroxy-6,8,12,16-tetramethyl-4,4-trimethylene-17-(2-methylthiazol-4-yl)-heptadeca-12,16-dien-5-one

Analogously to Example 1ar, 289 mg (86%) of the title compound isobtained from 381 mg (0.39 mmol) of the compound that is described under28t.

¹H-NMR (CDCl₃): δ=0.01 (3H), 0.05 (3H), 0.08 (3H), 0.11 (3H), 0.16 (3H),0.18 (3H), 0.90-1.00 (30H), 1.10 (3H), 1.67 (3H), 1.99 (3H), 2.20-2.40(3H), 2.71 (3H), 3.14 (1H), 3.63 (2H), 3.82 (1H), 4.09 (2H), 5.12 (1H),6.46 (1H), 6.92 (1H) ppm.

EXAMPLE 28v(3S,6R,7S,8S,12Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-6,8,12,16-tetramethyl-4,4-trimethylene-17-(2-methylthiazol-4-yl)-5-oxo-heptadeca-12,16-dien-1-al

Analogously to Example 1k, after filtration on silica gel, 284 mg (100%)of the title compound is obtained from 285 mg (0.34 mmol) of thecompound that is described under 28u.

EXAMPLE 28w(3S,6R,7S,8S,12Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-6,8,12,16-tetramethyl-4,4-trimethylene-17-(2-methylthiazol-4-yl)-5-oxo-heptadeca-12,16-dienoicacid

Analogously to Example 1at, after purification, 235 mg (81%) of thetitle compound is obtained from 284 mg (0.34 mmol) of the compound thatis described under 28v.

¹H-NMR (CDCl₃): δ=0.00 (3H), 0.02 (3H), 0.04 (3H), 0.09 (3H), 0.14 (3H),0.19 (3H), 0.87-0.96 (30H), 1.13 (3H), 1.70 (3H), 1.95 (3H), 2.12-2.30(3H), 2.70 (3H), 3.00 (1H), 3.80 (1H), 4.13 (1H), 4.49 (1H), 5.18 (1H),6.63 (1H), 6.93 (1H) ppm.

EXAMPLE 28x(3S,6R,7S,8S,12Z,15S,16E)-3,7-Bis-[[dimethyl)1,1-dimethylethyl)silyl]oxy]-15-hydroxy-17-(2-methylthiazol-4-yl)-6,8,12,16-tetramethyl-4,4-trimethylen-5-oxoheptadeca-12,16-dienoic Acid

Analogously to Example 1i, 200 mg (100%) of the title compound, which isused without purification in the next step, is obtained from 230 mg(0.27 mmol) of the compound that is described under 28w.

¹H-NMR (CDCl₃): δ=0.05 (3H), 0.10 (6H), 0.19 (3H), 0.90 (18H), 0.95(3H), 1.12 (3H), 1.70 (3H), 2.00 (3H), 2.70 (3H), 3.00 (1H), 3.84 (1H),4.15 (1H), 4.49 (1H), 5.15 (1H), 6.67 (1H), 6.91 (1H) ppm.

EXAMPLE 28y(4S,7R,8S,9S,13(Z),16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-methyl-2-(2-methylthiazol-4-yl)-ethenyl)-1-oxa-7,9,13-trimethyl-5,5-trimethylene-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1aw, after working-up, 101 mg (52%) of the titlecompound is obtained from 200 mg (0.27 mmol) of the compound that isdescribed under 28x.

¹H-NMR (CDCl₃): δ=−0.05 (3H), 0.12 (3H), 0.15 (6H), 0.82 (9H), 0.98(9H), 1.00 (3H), 1.24 (3H), 1.68 (3H), 2.11 (3H), 2.28 (1H), 2.47 (1H),2.60-2.70 (2H), 2.72 (3H), 2.98 (1H), 3.93 (1H), 4.41 (1H), 5.03 (1H),5.17 (3H), 6.58 (1H), 6.98 (1H) ppm.

EXAMPLE 28(4S,7R,8S,9S,13(Z),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-7,9,13-trimethyl-5,5-trimethylene-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 51 mg (73%) of the title compound is obtainedfrom 101 mg (0.14 mmol) of the compound that is described under 28y.

¹H-NMR (CDCl₃): δ=1.01 (3H), 1.28 (3H), 1.67 (3H), 2.09 (3H), 2.70 (3H),3.01 (1H), 3.73 (1H), 4.46 (1H), 5.14 (1H), 5.19 (1H), 6.60 (1H), 6.96(1H) ppm.

EXAMPLE 29(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10,12,16-trimethyl-8,8-trimethylene-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10,12,16-trimethyl-8,8-trimethylene-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 14, 29 mg (59%) of title compound A and 7 mg(14%) of title compound B are obtained after separation from 47 mg (0.09mmol) of the compound that is described under 28.

¹H-NMR (CDCl₃) of compound A: δ=1.01 (3H), 1.24 (3H), 1.28 (3H), 2.09(3H), 2.72 (3H), 2.78 (1H), 3.05 (1H), 3.72 (1H), 4.20 (1H), 4.45 (1H),5.37 (1H), 6.59 (1H), 6.96 (1H) ppm.

¹H-NMR (CDCl₃) of compound B: δ=0.94 (3H), 1.20 (3H), 1.26 (3H), 2.12(3H), 2.71 (3H), 2.99 (1H), 3.11 (1H), 4.41 (1H), 4.39 (1H), 5.60 (1H),6.62 (1H), 6.99 (1H) ppm.

EXAMPLE 30(4S,7R,8S,9S,13(E),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-7,9,13-trimethyl-5,5-trimethylene-cyclohexadec-13-ene-2,6-dioneEXAMPLE 30a(3S,6R,7S,8S,12E,15S,16E)-1,3,7,15-Tetrakis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-6,8,12,16-tetramethyl-4,4-trimethylene-17-(2-methylthiazol-4-yl)-heptadeca-12,16-dien-5-one

Analogously to Example 1aq, 230 mg (90%) of the title compound isobtained from 227 mg (0.27 mmol) of compound B that is described under28s.

¹H-NMR (CDCl₃): δ=0.01 (3H), 0.03 (3H), 0.04 (3H), 0.06 (3H), 0.08 (3H),0.11 (3H), 0.15 (3H), 0.17 (3H), 0.87-0.98 (39H), 1.06 (3H), 1.57 (3H),2.00 (3H), 2.20-2.39 (3H), 2.70 (3H), 3.09 (1H), 3.61 (2H), 3.78 (1H),4.10 (2H), 5.14 (3H), 6.45 (1H), 6.91 (1H) ppm.

EXAMPLE 30b(3S,6R,7S,8S,12E,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-1-hydroxy-6,8,12,16-tetramethyl-4,4-trimethylene-17-(2-methylthiazol-4-yl)-heptadeca-12,16-dien-5-one

Analogously to Example 1ar, 170 mg (84%) of the title compound isobtained from 230 mg (0.24 mmol) of the compound that is described under30a.

¹H-NMR (CDCl₃): δ=0.01 (3H), 0.06 (3H), 0.08 (3H), 0.10 (3H), 0.17 (3H),0.19 (3H), 0.85-1.00 (30H), 1.10 (3H), 1.62 (3H), 2.15-2.40 (3H), 2.71(3H), 3.12 (1H), 3.63 (2H), 3.79 (1H), 4.09 (2H), 5.13 (1H), 6.42 (1H),6.90 (1H) ppm.

EXAMPLE 30c(3S,6R,7S,8S,12E,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-6,8,12,16-tetramethyl-4,4-trimethylene-17-(2-methylthiazol-4-yl)-5-oxo-heptadeca-12,16-dien-1-al

Analogously to Example 1k, after filtration on silica gel, 170 mg (100%)of the title compound is obtained from 170 mg (0.20 mmol) of thecompound that is described under 30b.

EXAMPLE 30d(3S,6R,7S,8S,12E,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-4,4,6,8,12,16-tetramethyl-4,4-trimethylene-17-(2-methylthiazol-4-yl)-5-oxo-heptadeca-12,16-dienoicAcid

Analogously to Example 1at, after purification, 144 mg (83%) of thetitle compound is obtained from 170 mg (0.20 mmol) of the compound thatis described under 30c.

¹H-NMR (CDCl₃): δ=0.01 (3H), 0.05 (3H), 0.06 (3H), 0.09 (3H), 0.15 (3H),0.20 (3H), 0.85-1.00 (30H), 1.12 (3H), 1.55 (3H), 1.97 (3H), 2.71 (3H),3.09 (1H), 3.82 (1H), 4.10 (1H), 4.41 (1H), 5.11 (1H), 6.46 (1H), 6.95(1H) ppm.

EXAMPLE 30e(3S,6R,7S,8S,12E,15S,16E)-3,7-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-15-hydroxy-17-(2-methylthiazol-4-yl)-6,8,12,16-tetramethyl-4,4-trimethylen-5-oxoheptadeca-12,16-dienoic acid

Analogously to Example 1i, 121 mg (100%) of the title compound, which isused without purification in the next step, is obtained from 140 mg(0.16 mmol) of the compound that is described under 30d.

¹H-NMR (CDCl₃): δ=0.05 (3H), 0.09 (6H), 0.18 (3H), 0.85-0.95 (18H), 0.98(3H), 1.11 (3H), 1.61 (3H), 2.00 (3H), 2.69 (3H), 3.02 (1H), 3.82 (1H),4.15 (1H), 4.40 (1H), 5.15 (1H), 6.54 (1H), 6.91 (1H) ppm.

EXAMPLE 30f(4S,7R,8S,9S,13(E),16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-7,9,13-trimethyl-5,5-trimethylene-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1aw, after purification, 55 mg (48%) of the titlecompound is obtained from 121 mg (0.16 mmol) of the compound that isdescribed under 30e.

¹H-NMR (CDCl₃): δ=0.01 (3H), 0.09 (3H), 0.15 (6H), 0.92 (9H), 0.96 (9H),0.98 (3H), 1.26 (3H), 1.50 (3H), 2.19 (3H), 2.73 (3H), 2.91 (1H), 4.18(1H), 4.63 (1H), 5.09 (1H), 5.31 (1H), 6.53 (1H), 6.93 (1H) ppm.

EXAMPLE 30(4S,7R,8S,9S,13(E),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-7,9,13-trimethyl-5,5-trimethylene-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 27 mg (67%) of the title compound is obtainedfrom 55 mg (0.08 mmol) of the compound that is described under 30f.

¹H-NMR (CDCl₃): δ=1.03 (3H), 1.23 (3H), 1.55 (3H), 2.07 (3H), 2.72 (3H),3.04 (1H), 3.32 (1H), 3.51 (1H), 3.70 (1H), 4.46 (1H), 5.06 (1H), 5.49(1H), 6.59 (1H), 7.02 (1H) ppm.

EXAMPLE 31(1R,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10,12,16-trimethyl-8,8-trimethylene-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1S,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroXy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10,12,16-trimethyl-8,8-trimethylene-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 14, 10 mg (39%) of title compound A and 8 mg(31%) of title compound B are obtained after separation from 25 mg (0.05mmol) of the compound that is described under 30.

¹H-NMR (CDCl₃) of compound A: δ=1.02 (3H), 1.25 (3H), 1.27 (3H), 2.08(3H), 2.71 (3H), 2.84 (1H), 3.13 (1H), 3.72 (1H), 4.93 (1H), 5.51 (1H),6.68 (1H), 7.04 (1H) ppm.

¹H-NMR (CDCl₃) of compound B: δ=0.98 (3H), 1.27 (3H), 1.28 (3H), 2.11(3H), 2.89 (1H), 3.08 (1H), 3.70 (1H), 4.48 (1H), 5.43 (1H), 6.58 (1H),6.97 (1H) ppm.

EXAMPLE 32(4S,7R,8S,9S,13(Z),16S(E))-4,8-Dihydroxy-9,13-dimethyl-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5-trimethylene-cyclohexadec-13-ene-2,6-dioneEXAMPLE 32a1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]-α-propylcyclobutanemethanol

Analogously to Example 1l, after purification, 20.81 g (72%) of thetitle compound is obtained from 24.15 g (105.8 mmol) of the compoundthat is described under 28c.

¹H-NMR (CDCl₃): δ=0.09 (6H), 0.93 (9H), 0.95 (3H), 1.36 (3H), 1.48-1.80(3H), 1.87 (3H), 2.08 (1H), 3.18 (1H), 3.56 (1H), 3.72 (1H), 3.86 (1H)ppm.

EXAMPLE 32b1-[1-[[[Dimethyl(1,1-dimethylethyl)silyl]oxy]methyl]cyclobut-1-yl]-1-butanone

Analogously to Example 1k, after filtration on silica gel, 20.7 g (100%)of the title compound is obtained from 20.81 g (76.34 mmol) of thecompound that is described under 32a.

¹H-NMR (CDCl₃): δ=0.05 (6H), 0.88 (9H), 0.92 (3H), 1.59 (2H), 1.75-1.95(4H), 2.23-2.34 (2H), 2.43 (2H), 3.81 (2H) ppm.

EXAMPLE 32c 1-[1-(Hydroxymethyl)cyclobut-1-yl]-1-butanone

Analogously to Example 1i, after purification, 11.57 g (97%) of thetitle compound is obtained from 20.7 g (76.34 mmol) of the compound thatis described under 32b.

¹H-NMR (CDCl₃): δ=0.94 (3H), 1.64 (2H), 1.85-2.10 (4H), 2.29-2.43 (2H),2.53 (2H), 3.87 (2H) ppm.

EXAMPLE 32d 1-(1-Oxobutyl)cyclobutanecarbaldehyde

Analogously to Example 1k, after filtration on silica gel, 2.31 g (100%)of the title compound is obtained from 2.34 g (15 mmol) of the compoundthat is described under 32c.

¹H-NMR (CDCl₃): δ=0.92 (3H), 1.62 (2H), 1.85-2.01 (4H), 2.38-2.55 (6H),9.69 (1H) ppm.

EXAMPLE 32e (4S,5R)-3-(Bromoacetyl)-4-methyl-5-phenyloxazolidin-2-one

82 ml of a 2.5 molar solution of butyllithium in hexane is added to asolution of 33.06 g (186.6 mmol) of(4S,5R)-4-methyl-5-phenyloxazolidin-2-one in 500 ml of tetrahydrofuranwithin 30 minutes at −70° C. under argon. Then, a solution of 15.55 ml(187 mmol) of bromoacetyl chloride in 250 ml of tetrahydrofuran is addedin drops in such a way that the internal temperature does not exceed−65° C. Then, it is stirred for one more hour at −70° C. Then, thereaction mixture is poured onto 50 ml of saturated aqueous ammoniumchloride solution. 90 ml of saturated aqueous sodium bicarbonatesolution is then added, allowed to come to 25° C., diluted with waterand extracted with ethyl acetate. The organic phase is washed withsaturated aqueous sodium chloride solution, dried on sodium sulfate andchromatographed on silica gel. 42.32 g (76%) of the title compound isobtained.

¹H-NMR (CDCl₃): δ=0.95 (3H), 4.57 (2H), 4.80 (1H), 5.76 (1H), 7.2-7.5(5H) ppm.

EXAMPLE 32f[4S-[3(R*),4α,5α]]-3-[3-Hydroxy-1-oxo-3-[1-(1-oxobutyl)cyclobut-1-yl]propyl]-4-methyl-5-phenyloxazolidin-2-one

200 mg (1.5 mmol) of anhydrous lithium iodide is added to a suspensionof 5 g (40.68 mmol) of anhydrous chromium(II) chloride in 60 ml oftetrahydrofuran under argon. Then, a mixture of 5 g (16.77 mmol) of thecompound that is described under 32e and 2.31 g (15 mmol) of thecompound that is described under 32d is added to 10 ml oftetrahydrofuran (exothermal reaction, the internal temperature shouldnot exceed 35° C.). It is allowed to stir for one more hour at 25° C.,and then 50 ml of saturated aqueous sodium chloride solution is addedwith slight cooling. It is stirred for another 30 minutes at 25° C.Then, it is extracted with ethyl acetate. The organic phase is washedwith saturated aqueous sodium chloride solution, dried on sodium sulfateand chromatographed on silica gel. 3.89 g (69%) of the title compound isobtained.

¹H-NMR (CDCl₃): δ=0.90-0.99 (6H), 1.58-1.73 (4H), 1.79-2.05 (2H),2.10-2.69 (7H), 3.00-3.12 (2H), 3.44 (1H), 4.39 (1H), 4.78 (1H), 5.70(1H), 7.27-7.33 (2H), 7.35-7.48 (3H) ppm.

EXAMPLE 32g[4S-[3(R*),4α,5α]]-3-[3-[[Dimethyl(1,1-dimethylethyl)silyl]oxy]-1-oxo-3-[1-(1-oxobutyl)cyclobut-1-yl]propyl]-4-methyl-5-phenyloxazolidin-2-one

Analogously to Example 1aq, after purification, 3.94 g (76%) of thetitle compound is obtained from 3.89 g (10.42 mol) of the compound thatis described under Example 32f.

¹H-NMR (CDCl₃): δ=0.08 (3H), 0.20 (3H), 0.85-0.98 (15H), 1.55-1.93 (4H),2.03 (1H), 2.20-2.38 (3H), 2.45-2.67 (2H), 2.91-3.13 (2H), 4.62-4.75(2H), 5.67 (1H), 7.29-7.47 (5H) ppm.

EXAMPLE 32h(S)-3-[3-[[Dimethyl(1,1-dimethyl)silyl]oxy]-3-[1-(1-oxopropyl)cyclobut-1-yl]propanoicAcid

3.29 ml (32.3 mmol) of a 30% hydrogen peroxide solution (exothermalreaction, the internal temperature should not exceed 15° C.) is added toa solution of 3.94 g (8.08 mmol) of the compound, described under 32g,in 40 ml of a mixture of tetrahydrofuran and water (4:1) at 0° C. It isallowed to stir for 5 more minutes at 0° C., and then a solution of 309mg (32.3 mmol) of lithium hydroxide in 16 ml of water is added. Then, itis stirred for 3 more hours at 0° C. Then, the reaction mixture iscarefully poured onto ice-cold sodium thiosulfate solution. It isstirred for 5 more minutes at 0° C. and for 15 minutes at 25° C. Then,the tetrahydrofuran is drawn off in a vacuum, and the remaining solutionis acidified with 5N hydrochloric acid to pH=1. It is extracted withdichloromethane. The organic phase is washed with saturated aqueoussodium chloride solution, dried on sodium sulfate and chromatographed onsilica gel. 2.34 g (89%) of the title compound and 1.04 g(4S,5R)-4-methyl-5-phenyloxazolidin-2-one, which can be used again inExample 32e, is obtained.

¹H-NMR (CDCl₃): δ=0.09 (3H), 0.18 (3H), 0.86-0.97 (12H), 1.59 (2H),1.56-1.94 (3H), 2.05-2.36 (4H), 2.40-2.57 (3H), 4.44 (1H) ppm.

EXAMPLE 32i(3S,6R,7S,8S,12Z,15S,16E)-3,7,15-Tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-6-ethyl-8,12,16-trimethyl-4,4-trimethylene-17-(2-methylthiazol-4-yl)-5-oxo-heptadeca-12,16-dienoicacid (A) and(3S,6S,7R,8S,12E,15S,16E)-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-6-ethyl-8,12,16-trimethyl-4,4-trimethylene-17-(2-methylthiazol-4-yl)-5-oxo-heptadeca-12,16-dienoicacid (B) and(3S,6R,7R,8S,12Z,15S,16E)-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-6-ethyl-8,12,16-trimethyl-4,4-trimethylene-17-(2-methylthiazol-4-yl)-5-oxo-heptadeca-12,16-dienoicacid (C) and(3S,6S,7R,8S,12E,15S,16E)-3,7,15-tris-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-6-ethyl-8,12,16-trimethyl-4,4-trimethylene-17-(2-methylthiazol-4-yl)-5-oxo-heptadeca-12,16-dienoicAcid (D)

Analogously to Example 1ak, lithium diisopropylamide is produced from842 μl (5.99 mmol) of diisopropylamine and 3.74 ml (5.99 mmol) of a 1.6molar solution of butyllithium in hexane in 5 ml of absolutetetrahydrofuran. A solution of 787 mg (2.4 mmol) of the compound,described under 32h, in 5 ml of absolute tetrahydrofuran is added tothis solution at −78° C. It is stirred for one more hour at −40° C.Then, it is cooled again to −78° C., and a solution of 524 mg (1.2 mmol)of the compound, described under 28r, in 5 ml of absolutetetrahydrofuran is added. It is stirred for another hour at −78° C.Then, the reaction mixture is poured onto saturated aqueous ammoniumchloride solution, 0.45 ml of glacial acetic acid is added and allowedto stir for one more hour. Then, it is extracted with ethyl acetate. Theorganic phase is washed with saturated aqueous sodium chloride solution,dried on sodium sulfate and concentrated by evaporation in a vacuum. Thecrude product that is obtained (max. 920 mg (100%)) is dissolved in 10ml of dichloromethane and converted into the persilylated compoundanalogously to Example 1aq. The crude product that is thus obtained isdissolved in 30 ml of a 1:1 mixture of dichloromethane and methanol. 280mg (1.2 mmol) of DL-camphorsulfonic acid is added at 0° C. and allowedto stir for 2.5 more hours at this temperature. Then, 2.5 ml oftriethylamine is added. Then, it is concentrated by evaporation in avacuum. The residue is taken up in dichloromethane. It is washed with 1Nhydrochloric acid and saturated aqueous sodium chloride solution. It isdried on sodium sulfate and concentrated by evaporation in a vacuum. Thecrude product that is obtained is separated by repeated columnchromatography on silica gel. Obtained are: 229 mg (22%) of compound A,174 mg (17%) of compound B and 292 mg (28%) of a mixture of compounds Cand D.

¹H-NMR (CDCl₃) of compound A: δ=0.00 (3H), 0.02 (3H), 0.04 (3H), 0.08(3H), 0.13 (3H), 0.18 (3H), 0.85-0.99 (33H), 1.79 (3H), 1.94 (3H),2.10-2.28 (5H), 2.30-2.45 (2H), 2.48 (H), 2.70 (3H), 2.90 (1H), 3.78(1H), 4.17 (1H), 4.46 (1H), 5.19 (1H), 6.64 (1H), 6.95 (1H) ppm.

¹H-NMR (CDCl₃) of compound B: δ=0.00 (3H), 0.03 (3H), 0.06 (3H), 0.07(3H), 0.14 (3H), 0.19 (3H), 0.78-0.98 (33H), 1.55 (3H), 1.92 (3H),2.12-2.50 (10H), 2.69 (3H), 2.72 (1H), 3.00 (1H), 3.88 (1H), 4.08 (1H),4.41 (1H), 5.10 (1H), 6.48 (1H), 6.94 (1H) ppm.

EXAMPLE 32k(3S,6R,7S,8S,12Z,15S,16E)-3,7-Bis-[[dimethyl(1,1-dimethylethyl)-silyl]oxy]-15-hydroxy-17-(2-methylthiazol-4-yl)-6-ethyl-8,12,16-trimethyl-4,4-trimethylen-5-oxoheptadeca-12,16-dienoic acid

Analogously to Example 1i, 200 mg (100%) of the title compound, which isused without purification in the next step, is obtained from 229 mg(0.26 mmol) of compound A that is described under 32i.

EXAMPLE 32l(4S,7R,8S,9S,13(Z),16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)-silyl]oxy]-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-7-ethyl-9,13-trimethyl-5,5-trimethylene-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1aw, after purification, 100 mg (51%) of thetitle compound is obtained from 200 mg (0.26 mmol) of the compound thatis described under 32k.

¹H-NMR (CDCl₃): δ=0.93 (3H), 0.11 (3H), 0.16 (6H), 0.83 (9H), 0.88 (3H),0.96 (9H), 1.02 (3H), 1.68 (3H), 2.12 (3H), 2.30-2.70 (6H), 2.72 (3H),3.03 (1H), 4.07 (1H), 4.43 (1H), 5.01 (1H), 5.17 (1H), 6.58 (1H), 6.98(1H) ppm.

EXAMPLE 32(4S,7R,8S,9S,13(Z),16S(E))-4,8-Dihydroxy-9,13-dimethyl-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5-trimethylene-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, after purification, 63 mg (90%) of the titlecompound is obtained from 100 mg (0.13 mmol) of the compound that isdescribed under 32l.

¹H-NMR (CDCl₃): δ=0.95 (3H), 1.00 (3H), 1.68 (3H), 2.05 (3H), 2.72 (3H),2.97 (1H), 3.67 (1H), 4.46 (1H), 5.08 (1H), 5.23 (1H), 6.59 (1H), 6.98(1H) ppm.

EXAMPLE 33(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-12,16-dimethyl-10-ethyl-8,8-trimethylene-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1R,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-12,16-dimethyl-10-ethyl-8,8-trimethylene-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 14, 24 mg (47%) of title compound A and 6 mg(12%) of title compound B are obtained from 50 mg (0.10 mmol) of thecompound that is described under 32.

¹H-NMR (CDCl₃) of compound A: δ=0.95 (3H), 0.98 (3H), 1.30 (3H), 2.07(3H), 2.71 (3H), 2.76 (1H), 3.03 (1H), 3.69 (1H), 4.44 (1H), 5.40 (1H),6.58 (1H), 6.97 (1H) ppm.

¹H-NMR (CDCl₃) of compound B: δ=0.92 (3H), 0.95 (3H), 2.10 (3H), 2.71(3H), 2.88 (1H), 3.04 (1H), 3.78 (1H), 4.49 (1H), 5.53 (1H), 6.64 (1H),6.99 (1H) ppm.

EXAMPLE 34(4S,7R,8S,9S,13(E),16S(E))-4,8-Dihydroxy-9,13-dimethyl-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5-trimethylene-cyclohexadec-13-ene-2,6-dioneEXAMPLE 34a(3S,6R,7S,8S,12E,15S,16E)-3,7-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-15-hydroxy-17-(2-methylthiazol-4-yl)-6-ethyl-8,12,16-trimethyl-4,4-trimethylen-5-oxo-heptadeca-12,16-dienoicacid

Analogously to Example 1i, 151 mg (100%) of the title compound, which isused without purification in the next step, is obtained from 174 mg(0.20 mmol) of compound B that is described under Example 32i.

EXAMPLE 34b(4S,7R,8S,9S,13(E),16S(E))-4,8-Bis-[[dimethyl(1,1-dimethylethyl)silyl]oxy]-16-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-7-ethyl-9,13-trimethyl-5,5-trimethylene-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1aw, after purification, 86 mg (58%) of the titlecompound is obtained from 151 mg (0.20 mmol) of the compound that isdescribed under 34a.

¹H-NMR (CDCl₃): δ=0.04 (3H), 0.11 (6H), 0.13 (3H), 0.86 (3H), 0.88 (9H),0.93 (9H), 1.01 (3H), 1.54 (3H), 2.17 (3H), 2.24-2.46 (3H), 2.72 (3H),2.83 (1H), 3.03 (1H), 4.08 (1H), 4.53 (1H), 5.13 (1H), 5.27 (1H), 6.53(1H), 6.96 (1H) ppm.

EXAMPLE 34(4S,7R,8S,9S,13(E),16S(E))-4,8-Dihydroxy-9,13-dimethyl-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5-trimethylene-cyclohexadec-13-ene-2,6-dione

Analogously to Example 1, 39 mg (65%) of the title compound is obtainedfrom 86 mg (0.12 mmol) of the compound that is described under 34b.

¹H-NMR (CDCl₃): δ=0.93 (3H), 1.06 (3H), 1.53 (3H), 2.03 (3H), 2.69 (3H),3.09 (1H), 3.82 (1H), 4.52 (1H), 5.03 (1H), 5.36 (1H), 6.60 (1H), 7.03(1H) ppm.

EXAMPLE 35(1R,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-12,16-dimethyl-10-ethyl-8,8-trimethylene-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(A) and(1S,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-12,16-dimethyl-10-ethyl-8,8-trimethylene-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(B)

Analogously to Example 14, 10 mg (32%) of title compound A and 8 mg(26%) of title compound B are obtained from 30 mg (0.06 mmol) of thecompound that is described under Example 34.

¹H-NMR (CDCl₃) of compound A: δ=0.95 (3H), 1.03 (3H), 1.23 (3H), 2.08(3H), 2.71 (3H), 2.84 (1H), 3.16 (1H), 3.82 (1H), 4.52 (1H), 5.50 (1H),6.72 (1H), 7.06 (1H) ppm.

¹H-NMR (CDCl₃) of compound B: δ=0.93 (3H), 0.98 (3H), 1.22 (3H), 2.06(3H), 2.70 (3H), 2.88 (1H), 3.05 (1H), 3.62 (1H), 4.46 (1H), 5.41 (1H),6.60 (1H), 6.96 (1H) ppm.

1. A compound which is:(4S,7R,8S,9S,13(Z),16S(E))-4,8-Dihydroxy-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione,(4S,7R,8S,9S,13E,16S(E))-4,8-dihydroxy-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione(B),(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(1R,3S(E),7S,10R,11S,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(1S,3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(1R,3S(E),7S,10R,11S,12S,16R)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(4S,7S,8R,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione,(4S,7S,8R,9S,13E,16S(E))-4,8-dihydroxy-7-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione,(1S,3S(E),7S,10S,11R,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(1R,3S(E),7S,10S,11R,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(1S,3S(E),7S,10S,11R,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(1R,3S(E),7S,10S,11R,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(4S,7R,8S,9S,13(E orZ),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-7-phenyl-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione,(1(S orR),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-phenyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(1(R orS),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-phenyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(4S,7R,8S,9S,13(E orZ),16S(E))-7-Benzyl-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione,(4S,7R,8S,9S,13E,16S(E))-4,8-dihydroxy-7-ethyl-16(1-methyl-2-(2-thiazolyi)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione,(1S,3S(E),7S,10S,11R,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(1R,3S(E),7S,10S,11R,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(1S,3S(E),7S,10S,11R,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(1R,3S(E),7S,10S,11R,12S,16S)-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(4S,7R,8S,9S,13(E orZ),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-7-phenyl-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione,(1(S orR),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-phenyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(1R orS),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-10-phenyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(4S,7R,8S,9S,13(E orZ),16S(E))-7-Benzyl-4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione,(1(S orR),3S(E),7S,10R,11S,12S,16R)-10-Benzyl-7,11-dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(4S,7R,8S,9S,11E/Z,13(E orZ),16S(E))-4,8-Dihydroxy-13-ethyl-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,7,9-tetramethyl-cyclohexadec-11,13-diene-2,6-dione(1(S orR),3S(E),7S,10R,11S,12S,14E/Z,16R)-7,11-Dihydroxy-16-ethyl-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadec-14-ene-5,9-dione,(1R orS),3S(E),7S,10R,11S,12S,14E/Z,16S)-7,11-Dihydroxy-16-ethyl-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadec-14-ene-5,9-dione,(4S,7R,8S,9S,11E/Z,13(E orZ),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-13-propyl-5,5,7,9-tetramethyl-cyclohexadec-11,13-diene-2,6-dione,(1(S orR),3S(E),7S,10R,11S,12S,14E/Z,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-16-propyl-8,8,10,12-tetramethyl-4,17-dioxabicycbo[14.1.0]heptadec-14-ene-5,9-dione,(1R orS),3S(E),7S,10R,11S,12S,14E/Z,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-16-propyl-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadec-14-ene-5,9-dione,(4S,7R,8S,9S,13(E orZ),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,7,13-tetramethyl-9-trifluoromethyl-cyclohexadec-13-ene-2,6-dione,(1(SorR),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,16-tetramethyl-12-trifluoromethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(1R orS),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,16-tetramethyl-12-trifluoromethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione,(4S,7R,8S,9S,13(E orZ),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-5,5,7,9-tetramethyl-13-trifluoromethyl-cyclohexadec-13-ene-2,6-dione,(1(S orR),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12-tetramethyl-16-trifluoromethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,(1R orS),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-8,8,10,12-tetramethyl-16-trifluoromethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,(4S,7R,8S,9S,13(E orZ),16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-1-oxa-13-pentafluoroethyl-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione,(1(S orR),3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-16-pentafluoroethyl-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione,(1R orS),3S(E),7S,10R,11S,12S,16S)-7,11-Dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl)-16-pentafluoroethyl-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadeca-5,9-dione.